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Otorhinolaryngologic manifestations of Hartsfield syndrome: Case series and review of literature
International Journal of Pediatric Otorhinolaryngology 98 (2017) 4e8
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: http://www.ijporlonline.com/
Case Report
Otorhinolaryngologic manifestations of Hartsfield syndrome: Case series and review of literature* Jeremie D. Oliver, BS, BA a, Deanna C. Menapace, MD b, Shelagh A. Cofer, MD b, * a b
Mayo Clinic School of Medicine, Rochester, MN, USA Department of Otorhinolaryngology, Mayo Clinic, Rochester, MN, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 March 2017 Received in revised form 20 April 2017 Accepted 21 April 2017 Available online 24 April 2017
Diagnosis of Hartsfield syndrome includes recognition of three distinct clinical anomalies: holoprosencephaly, ectrodactyly, and bilateral cleft-lip and palate syndrome. A family including three male siblings all affected by Hartsfield syndrome presented to our institution for care. An autosomal dominant variant in Fibroblast Growth Factor Receptor 1 (FGFR1) was identified. This report focuses on otorhinolaryngologic manifestationsof Hartsfield syndrome, previously undescribed, including midline defects of holoprosencephaly, bilateral cleft-lip and palate, retrognathia, gastroesophageal reflux disease, external ear anomalies, eustachian tube dysfunction, and midface abnormalities, in addition to multidisciplinary, long-term management strategies. Multidisciplinary management is imperative in the care of these children with modification of approach based on their medical complexity. © 2017 Elsevier B.V. All rights reserved.
Keywords: Hartsfield syndrome Holoprosencephaly Ectrodactyly Microtia Cupped-ear deformity FGFR1 gene Cleft-lip and palate
1. Introduction To date, there have been fewer than 20 cases of Hartsfield syndrome documented in the English literature [1]. Clinically, Hartsfield syndrome has been associated with the presentation of three distinct findings: holoprosencephaly, ectrodactyly, and bilateral cleft lip-palate. Variants in FGFR1, encoding a receptor critical for signaling is the only known gene associated with this condition [2]. The holoprosencephaly is primarily associated with failed or incomplete forebrain development early in gestation; as a result, microcephaly, global developmental delay, spasticity, seizures, and feeding difficulties are common [1,2]. 2. Case report After receiving Mayo Clinic IRB approval (IRB#17e001011) a
* This project was accepted for poster presentation at the upcoming American Association of Facial Plastic and Reconstructive Surgery section meeting at the Combined Otolaryngology Spring Meeting (COSM) in San Diego, CA this April 26e30, 2017. * Corresponding author. Department of Otorhinolaryngology, Mayo Clinic, 200 1st St SW Rochester, MN 55905 USA. E-mail address: [email protected] (S.A. Cofer).
http://dx.doi.org/10.1016/j.ijporl.2017.04.035 0165-5876/© 2017 Elsevier B.V. All rights reserved.
case series review was performed including three male siblings affected by Hartsfield syndrome as they presented for care. The eldest sibling presented at six years of age with holoprosencephaly, bilateral epicanthal folds, repaired bilateral cleftlip and palate, nasal clefting, retrognathiaa, a single central incisor, bilateral hand and foot ectrodactyly, global developmental delay, microcephaly, broad nasal bridge, bilateral microtia (grade 3 on right, grade 1 on left), unilateral aural atresia, right ear skin tag and a pit behind the ear, and malar hypoplasia. He has already undergone previous surgical interventions at an outside institution, including bilateral cleft-lip and palate repair and placement of multiple tympanostomy tubes. An audiogram confirmed a mild conductive hearing loss on the left and a maximum conductive hearing loss on the right. Otorhinolaryngology was asked to evaluate and manage his microtia and aural atresia. Recommendations were given to perform elective otoplasty with cartilage crafting as well as conchal setback. The middle son was diagnosed with Hartsfield syndrome on prenatal ultrasound. He was born at 39 4/7 weeks by vaginal delivery. At birth, he was identified to have low-set cupped-ears, auricular skin tags, severe bilateral cleft-lip and palate, nasal tip clefting, retrognathia and bilateral ectrodactyly of the hands and feet. Aerodigestive concerns were paramount, and initial attempts
J.D. Oliver et al. / International Journal of Pediatric Otorhinolaryngology 98 (2017) 4e8
at oral feeding with a Haberman feeder were unsuccessful; orogastric feeds were supplemented. A vinyl polysiloxane palatal obturator made by a prosthodonthist was placed to facilitate oral feeding. Early gastrostomy tube was placed at seventeen days of to facilitate nutrition and electrolyte balance per multidisciplinary recommendations of the otorhinolaryngology and endocrinology teams. Pre-surgical infant orthopedics of the bilateral cleft-lip was then completed with passive technique and taping of the upper lip. It should be noted that nasoalveolar molding (NAM) was attempted but not tolerated by this medically complex child. Bilateral cleft-lip was repaired at 10 weeks and the patient was discharged when medically stable. At seven months of age, tympanostomy tubes were placed to treat bilateral middle ear effusions and a moderate conductive hearing loss. The child's comorbidities included holoprosencephaly, diabetes insipidus, micropenis and mild juxtaductal coarctation of the aorta with care provided by General Surgery, Cardiothoracic Surgery, Endocrinology, and Neurology for multidisciplinary management. At ten days of age the patient underwent repair of coarctation of the aorta and extended end-to-end anastomosis with ligation of the ductus arteriosus. Unfortunately, at 18 months of age, he passed away, due to an upper respiratory illness associated with metabolic derangements and suspected cardiopulmonary event. The youngest sibling, also diagnosed in utero, presented at birth with hypertelorism, retrognathia, bilateral cleft-lip and palate, nasal clefting, nasal glioma, cupped-ear deformity and ectrodactyly. Similarly as the case above, a pre-emptive gastrostomy tube was placed at 2 weeks of age. He then underwent simultaneous cleft lip repair and nasal glioma excision at 10 weeks of age. Unfortunately, he was lost to follow-up for a short period of time after his sibling passed away, and his secondary craniofacial repairs were delayed. Cleft-palate repair with simultaneous bilateral myringotomy with tympanostomy tube placement then occurred at two years of age, accompanied by closely monitored electrolyte levels perioperatively. His post-operative course was complicated by palate repair dehiscence, gastrostomy tube feeding intolerance and electrolyte abnormalities. An effort to salvage the palate repair with re-repair was performed using permanent sutures and hyperbaric oxygen therapy, but was unsuccessful. His comorbidities include semilobar holoprosencephaly, diabetes insipidus and coarctation of the aorta. Endocrinology closely monitors his electrolyte balance, while Neurology accompanies his progress peripherally. He remains stable and closely monitored with plans to revise the cleft-palate. In summary, the characteristic phenotypic findings appreciated
5
in the family reported are listed in Table 1 and seen in Fig. 1 (see Table 2). 3. Discussion Hartsfield syndrome includes holoprosencephaly (HPE), ectrodactyly, and bilateral cleft lip-palate syndrome. The first case was described by Dr. J.K. Hartsfield, Jr. in 1984 [3], and there have been fewer than 20 cases reported in the literature to date. It is important to recognize this distinct syndrome in the otorhinolaryngology literature. Hartsfield syndrome features of cleft lip-palate and HPE syndromes are similar to important developmental syndromes, including Smith-Lemli-Opitz syndrome (SLOS), Pallister-Hall syndrome, as well as the group of p63-related disorders such as ectrodactylyeectodermal dysplasia-clefting (EEC) syndrome and Hay Wells (AEC) syndrome, and facial clefts and brachial amelia. However, Hartsfield syndrome has unique characteristics helping to uniquely define this syndrome. The cases were reported in this series, in an attempt to further define characteristics of this population and to improve in the future cares of these complex patients as more is identified about this complex disease process. The family reported in this case series has four male siblings, three of which harbor the FGFR1 variant c.1880G > C(p.Arg627Thr) and are affected by the disease. Interestingly, the patients' father was identified to have gonosomal mosaicism for this variant in sperm but not in blood or saliva and his sons display the complete genetic genotype [2]. No one in their family displayed effects of or was previously diagnosed with this condition. There are few cases scattered in the literature describing other associated genetic anomalies. However, the otorhinolaryngologic manifestations and implications of Hartsfield syndrome have not been reported previously. These findings are evolving, but as currently known a summary of the reported genetic and phenotypic findings has been included in Fig. 1. 4. Diagnosis and management 4.1. In-utero diagnosis Prenatal ultrasonography should be utilized to detect the presence of holoprosencephaly, ectrodactyly, and cleft-lip and palate in the affected fetus [2]. This diagnostic method was successfully used to detect these signs of Hartsfield syndrome in the youngest sibling in this case series. Several previously-reported cases of suspected
Table 1 Summary of otorhinolaryngologic findings in all three siblings. Patient Sex, DOB
Ectrodactyly
Cleft-lip & palate
Facial dysmorphism
Ear anomalies
M, 7/31/2007
Bilateral hand and foot
Bilateral Cleft lip Cleft palate
M, 8/13/2014
Bilateral hand and foot
Bilateral Cleft lip Cleft palate
M, 2/11/2015(deceased)
Bilateral hand and foot
Bilateral Cleft lip Cleft palate
Hypertelorism Bilateral epicanthal folds Malar and midface hypoplasia Nasal tip clefting Central incisor Retrognathia Hypertelorism Bilateral epicanthal folds Malar and midface hypoplasia Nasal glioma Nasal tip clefting Retrognathia Hypertelorism Bilateral epicanthal folds Malar and midface hypoplasia Nasal tip clefting Retrognathia Glossoptosis
Low-set ears Bilateral microtia Unilateral aural atresia Cupped-ear deformity Auricular skin tag Auricular pit Low-set ears Cupped-ear deformity
Low-set ears Cupped-ear deformity Auricular skin tag
6
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Table 2 Summary of all patients in the literature with Hartsfield syndrome documented to date identifying sex, country or origin and genetic anomalies [1,2,4e10]. Key: FGFR1eFibroblast Growth Factor Receptor 1; SHH e Sonic Hedgehog; SIX3 - SIX Homeobox 3; ZIC2 - Zinc finger of the cerebellum (ZIC) protein 2; TGIF - TGFB-induced factor; FISH e Fluorescence in situ hybridization; TP63 - transformation-related protein 63; GLI2 - GLI Family Zinc Finger 2; SLC25A43 - Solute Carrier Family 25 Member 43; SLC25A5eSolute Carrier Family 25 Member 5; CXorf56 - Chromosome X Open Reading Frame 56; UBE2A - Ubiquitin Conjugating Enzyme E2 A; KAL1 - Kallmann syndrome 1 sequence. Patient sex, age at diagnosis
Author
Country
Genetic testing/Mutations
Clinical anomalies
M, 5 years
Dhamija et al 2014 Dhamija et al 2014 Dhamija et al 2014 El Hawrani et al 2005 Kalil and Fargalley 2012 Keaton et al 2010 Keaton et al 2010 Keaton et al 2010 Vilain et al 2009
USA
FGFR1
USA
FGFR1
USA
FGFR1
Canada
Not Known
Ectrodactyly, bilateral cleft lip and cleft palate, hypertelorism, retrognathia, bilateral microtia Ectrodactyly, bilateral cleft lip and cleft palate, hypertelorism, retrognathia, low-set ears Ectrodactyly, bilateral cleft lip and cleft palate, hypertelorism, retrognathia, low-set ears Hypotelorbitism, midline cleft lip, midline facial dysplasia
Egypt
Not Known
USA
No mutations in SHH,SIX3, ZIC2, or TGIF
USA
Not Known
Ectrodactyly, unilateral (right) cleft lip and cleft palate, dry rough skin with sparse, hypopigmented hair Ectrodacyly, bilateral cleft lip and palate, hypertelorsim, bilateral microtia, micropenis Ectrodactyly, midline cleft lip and palate
USA
Normal FISH for 7q21.3. No mutations in TP63
Ectrodactyly, hypotelorism, right ear overfolded
Belgium
Not Known
Ectrodactyly, unilateral (left) cleft lip and cleft palate, hypertelorism, right ear malformation Ectrodactyly, micropenis, cryptorchidism Ectrodactyly, bilateral cleft lip and palate, hypertelorism left preauricular skin tag, small external genitalia Ectrodactyly, midline cleft lip and cleft palate, hypotelorism, low-set ears Ectrodactyly, bilateral cleft lip and cleft palate, hypertelorism, left pre-auricular skin tag, small external genitalia, Ectrodactyly of the hands only, bilateral cleft lip and cleft palate, depressed nasal bridge, micropenis Facial dysmorphism, ectrodactyly, profound left-sided hypoacusis, micropenis Ectrodactyly, bilateral cleft lip and cleft palate, right-sided microtia
M, at birth M, at birth M, 4 months F, 11 months M, 2 years F, 24 weeks gestation F, not reported M, 24 weeks gestation M, 2 years M, at birth
Vilain et al 2009 Belgium Vilain et al 2009 Belgium
No GLI2 or TP63mutations. No GLI2 or TP63mutations.
M, at birth
Vilain et al 2009 Belgium
No GLI2 or TP63mutations.
M, at birth
Vilain et al 2009 Belgium
No GLI2 or TP63mutations.
M, at birth
Takenouchi et al Japan 2012 skaSowin Poland Seidler et al 2014 Prasad et al 2016 United Kingdom Hartsfield et al USA 1984
210 kb duplication of Xq24, involving genes SLC25A43, SLC25A5, CXorf56, and UBE2A Duplication of 110,967 bp onXp22.31, KAL1 overexpression p.Asn628Ser, impairment of FGFR1 kinase activity
M, 12 years M, at birth M, at birth
Not Known
Hartsfield syndrome have emphasized the usefulness of fetal brain imaging in the differential diagnosis of syndromal-clefting diagnosed in-utero, particularly when ectrodactylyeectodermal dysplasia-clefting syndrome is suspected [4]. Additionally, previous prenatal ultrasonography studies of affected fetuses have demonstrated measurements appropriate for gestational age, brain structures consistent with lobar holoprosencephaly, splaying of the cerebellar vermis, midline facial cleft, absence of a definitive nose, normal upper extremities, dysmorphic spine with hemivertebrae and several areas of lordosis and kyphosis extending from the cervical through lumbar regions. Normal external genitalia has been documented previously, however micropenis or underdevelopment of female genitalia has also been reported [5]. In the siblings included in this report, fetal echocardiogram has shown the presence of an interrupted aortic arch, coarctation of the aorta, and ventricular septal defects. 4.2. Otologic considerations It is recommended that routine newborn hearing screening be performed per state health guidelines with early referral to an Otolaryngologist when the diagnosis of Hartsfield syndrome is made. For the Otorhinolaryngologist, if aural atresia is present, consider an aural rehabilitation device such as a bone-conduction hearing device or BiCros hearing aid by three months of age. For microtia spectrum, six years old is the accepted age at which to perform reconstruction [6]. Likewise, patients with Hartsfield syndrome display various degrees of microtia and cupped-ear
Ectrodactyly, unilateral (right) cleft lip and cleft palate, hypertelorism, low-set ears
deformity. However, repair is elective, and should be performed only if the patient is medically stable. In particular with this syndrome, electrolyte management should take precedence. Consideration should also be made for tympanostomy tube placement, based on chronic otitis media with effusion, an essentially universal finding seen in our patients. The aforementioned otologic abnormalities may result in varying degrees of conductive hearing loss. No vestibulocochlear anomalies have been identified in those affected with Hartsfield syndrome, thus routine imaging for these types of anomalies is likely unnecessary although are likely obtained regardless in the setting of microtia. Sensorineural hearing loss has not been reported. 4.3. Cleft-lip and palate management In Hartsfield syndrome, the degree of clefting is severe, and consequently, columellar length in this patient population is drastically shortened to the point of near agenesis, which makes for particularly difficult cleft-lip nasal repair. Primary cleft-lip repair may be undertaken within the normal 10 week window provided the patient is medically stable. Recommended pre-operative consults include Endocrinology, Nutrition, and Airway Management, to ensure the patient can tolerate the procedure. Pre-surgical infant orthopedics, including passive taping and obturator placement with or without nasoalveolar molding may be attempted prior to cleft-lip and palate repair. Bilateral straight line closure technique was employed for a “cut-as-you-go”, tissue-sparing approach. Consideration must be paid to the large premaxillary segment
J.D. Oliver et al. / International Journal of Pediatric Otorhinolaryngology 98 (2017) 4e8
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Fig. 1. Image panel of three siblings presenting with Hartsfield syndrome. 1a - Grade 3 microtia (top left); 1b - Aural atresia (top middle); 1c - Cupped-ear deformity (top right); 2a - Bilateral cleft lip with dynacleft tape (middle left); 2b - Obturator placement and nasal clefting (middle middle); 2c - Nasal glioma (middle right); 3a,b - Ectrodactyly hands (bottom left and middle); 3c - Ectrodactyly foot (bottom right).
protrusion which makes primary orbicularis oris repair challenging. Severe hypolasia of the nasal tip cartilages should be addressed by utilizing primary rhinoplasty techniques at time of cleft-lip repair. Single dome and intradomal sutures may be performed at time of cleft-lip repair to improve nasal tip clefting and tip position. It is important to be aware of poor wound healing in the premaxillary segment in these patients. Minimalistic dissection is encouraged. Delayed palate repair is recommended to allow for growth prior to reconstruction. In our experience, clefting seen in this patient population is extremely wide and subject to high-tension closures. In performing cleft-palate repair, a two-flap palatoplasty approach
was taken utilizing bilateral vomer flaps. A nasoalveolar molding or a latham appliance is therefore helpful if tolerated. 4.4. Aerodigestive considerations Clinical presentation of the bilateral cleft-lip and palate with retrognathia in Hartsfield syndrome should alert the clinician to aspiration and obstruction risks. Oral and nasal airway may be difficult to use in these patients secondary to severe cleft-lip and palate. However, with orthopedic appliances in place they may still be safely attempted. Tongue-lip adhesion or tracheostomy could be
8
J.D. Oliver et al. / International Journal of Pediatric Otorhinolaryngology 98 (2017) 4e8
considered to facilitate airway patency, although no patient in this series required it. Similarly, we have not identified obstructive sleep apnea as a significant comorbiditiy in the cases presented here, nor in literature review. Difficulty coordinating suck-and-swallow secondary to central delays and severe clefting is seen in Hartsfield syndrome. Palatal obturator placement can facilitate nasogastric tube placement while oral feeds are attempted with a specialized cleft-feeder. However, ultimately, strong consideration should be given to early gastrostomy tube placement, not only to facilitate feeding but to help manage extreme electrolyte disturbances often seen with systemic illness and dehydration in these patients perioperatively. Routine microdirect laryngoscopy can be performed at the time of cleft-lip repair or cleft-palate repair, if the procedure is indicated.
were referred to Cardiothoracic Surgery for repair without complication.
4.5. Endocrinologic considerations
Financial disclosures
Those affected with Hartsfield syndrome are at risk for central diabetes insipidus, hypogonadotropic hypogonadism, and other dysfunction of the hypothalamic pituitary axis. From an endocrinologic standpoint, this syndrome is often characterized by these abnormalities. Given the potential severity of these endocrinologic dysfunctions, daily follow-up by Endocrinology is recommended to ensure continued monitoring of the urine output as well as a serum sodium and simultaneous serum and urine osmolality. To better assess the rest of the hypothalamic pituitary axis, it is recommended to measure free T4, TSH, LH, FSH, testosterone, and random growth hormone levels. If the patient does have increasing sodium or increasing urine output, in particular exceeding 5 mL/kg per hour, it is recommended to initiate desmopressin treatment. Desmopressin can be administered by a variety of routes including subcutaneous, nasal, or oral to control central diabetes insipidus. 4.6. Multidisciplinary care Multidisciplinary management of pertinent symptoms is fundamental to the successful treatment of Hartsfield syndrome. Clinical geneticists provide diagnostic evaluations and genetic testing to identify the underlying cause of the condition. Genetic counseling provides understanding of the mechanism of inheritance and the chance for familial recurrence. While most patients have autosomal dominant inheritance and a de novo mechanism is implied, gonosomal mosaicism, which in this case was paternal, can be the source of recurrence [2]. Although not highlighted here, a plastic surgeon may be involved in the craniofacial repair and/or the management of ectrodactyly. Prosthodontics, General Surgery, and speech and swallow specialists will be crucial in aiding in the mode of alimentation, setting the foundation for stable electrolyte measures. Similarly, Endocrinology is also crucial in the management of holoprosencephaly sequelae including diabetes insipidus. Two of our patients had confirmed cardiac defects, for which they
5. Conclusion Hartsfield syndrome is exceedingly rare, as evidenced by the limited number of documented cases to date. Accurate diagnosis of this disease can be achieved through prenatal ultrasound and through identification of post-natal holoprosencephaly, cleft-lip and palate and ectrodactyly. The Otolaryngologist's recognition of this condition as well as management of the bilateral cleft-lip and palate, retrognathia, nasal clefting, external ear anomalies, and eustachian tube dysfunction, is critical in the care of those affected by Hartsfield syndrome.
None. Acknowledgements We would like to thank Dr. Lisa Schimmenti for her help with the genetic analysis of this report. References [1] M. Kalil, K. Abbass, H.S. Fargalley, Holoprosencephaly in an Egyptian baby with ectrodactyly-ectodermal dysplasia-cleft syndrome: a case report, J. Med. Case Rep. 6 (2012) 35. [2] R. Dhamija, S. Kirmani, X. Wang, et al., Novel de novo heterozygous FGFR1 mutation in two siblings with hartsfield syndrome: a case of gonadal mosaicism, Am. J. Med. Genet. Part A 9 (2014) 2356e2359. [3] J.K. Hartsfield, D. Bixler, W.E. DeMeyer, Syndrome identification case report 119: hypertelorism associated with holoprosencephaly and ectrodactyly, Clin. Dysmorphol. 2 (1984) 27e31. [4] A. El-Hawrani, M. Sohn, M. Noga, H. El-Hakim, The face does predict the braindmidline facial and forebrain defects uncovered during the investigation of nasal obstruction and rhinorrhea: case report and a review of holoprosencephaly and its classifications, Int. J. Pediatr. Otorhinolaryngology 70 (2006) 935e940. [5] A.A. Keaton, B.D. Solomon, A.J. Van Essen, et al., Holoprosencephaly and ectrodactyly: report of three new patients and review of the literature, Am. J. Med. Genet. Seminars Med. Genet. 154C (2010) 170e175. [6] M. Abdel-Aziz, Congenital aural atresia, J. Craniofacial Surg. 24 (2013) 418e422. [7] C. Vilain, G. Mortier, G. Van Vliet, et al., Hartsfield holoprosencephalyectrodactyly syndrome in 5 male patients: further delineation and review, Am. J. Med. Genet. Part A 149 (2009) 1476e1481. [8] T. Takenouchi, H. Okuno, R. Kosaki, et al., Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting, Am. J. Med. Genet. Part A 158 (2012) 2537e2541. ska-Seidler, M. Piwecka, E. Olech, et al., Hyperosmia, ectrodactyly, [9] A. Sowin mild intellectual disability, and other defects in a male patient with an Xlinked partial microduplication and overexpression of the KAL1 gene, J. Appl. Genet. 56 (2014) 177e184. [10] R. Prasad, C. Brewer, C.P. Burren, Hartsfield syndrome associated with a novel heterozygous missense mutation in FGFR1 and incorporating tumoral calcinosis, Am. J. Med. Genet. Part A 170 (2016) 2222e2225.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: http://www.ijporlonline.com/
Case Report
Otorhinolaryngologic manifestations of Hartsfield syndrome: Case series and review of literature* Jeremie D. Oliver, BS, BA a, Deanna C. Menapace, MD b, Shelagh A. Cofer, MD b, * a b
Mayo Clinic School of Medicine, Rochester, MN, USA Department of Otorhinolaryngology, Mayo Clinic, Rochester, MN, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 March 2017 Received in revised form 20 April 2017 Accepted 21 April 2017 Available online 24 April 2017
Diagnosis of Hartsfield syndrome includes recognition of three distinct clinical anomalies: holoprosencephaly, ectrodactyly, and bilateral cleft-lip and palate syndrome. A family including three male siblings all affected by Hartsfield syndrome presented to our institution for care. An autosomal dominant variant in Fibroblast Growth Factor Receptor 1 (FGFR1) was identified. This report focuses on otorhinolaryngologic manifestationsof Hartsfield syndrome, previously undescribed, including midline defects of holoprosencephaly, bilateral cleft-lip and palate, retrognathia, gastroesophageal reflux disease, external ear anomalies, eustachian tube dysfunction, and midface abnormalities, in addition to multidisciplinary, long-term management strategies. Multidisciplinary management is imperative in the care of these children with modification of approach based on their medical complexity. © 2017 Elsevier B.V. All rights reserved.
Keywords: Hartsfield syndrome Holoprosencephaly Ectrodactyly Microtia Cupped-ear deformity FGFR1 gene Cleft-lip and palate
1. Introduction To date, there have been fewer than 20 cases of Hartsfield syndrome documented in the English literature [1]. Clinically, Hartsfield syndrome has been associated with the presentation of three distinct findings: holoprosencephaly, ectrodactyly, and bilateral cleft lip-palate. Variants in FGFR1, encoding a receptor critical for signaling is the only known gene associated with this condition [2]. The holoprosencephaly is primarily associated with failed or incomplete forebrain development early in gestation; as a result, microcephaly, global developmental delay, spasticity, seizures, and feeding difficulties are common [1,2]. 2. Case report After receiving Mayo Clinic IRB approval (IRB#17e001011) a
* This project was accepted for poster presentation at the upcoming American Association of Facial Plastic and Reconstructive Surgery section meeting at the Combined Otolaryngology Spring Meeting (COSM) in San Diego, CA this April 26e30, 2017. * Corresponding author. Department of Otorhinolaryngology, Mayo Clinic, 200 1st St SW Rochester, MN 55905 USA. E-mail address: [email protected] (S.A. Cofer).
http://dx.doi.org/10.1016/j.ijporl.2017.04.035 0165-5876/© 2017 Elsevier B.V. All rights reserved.
case series review was performed including three male siblings affected by Hartsfield syndrome as they presented for care. The eldest sibling presented at six years of age with holoprosencephaly, bilateral epicanthal folds, repaired bilateral cleftlip and palate, nasal clefting, retrognathiaa, a single central incisor, bilateral hand and foot ectrodactyly, global developmental delay, microcephaly, broad nasal bridge, bilateral microtia (grade 3 on right, grade 1 on left), unilateral aural atresia, right ear skin tag and a pit behind the ear, and malar hypoplasia. He has already undergone previous surgical interventions at an outside institution, including bilateral cleft-lip and palate repair and placement of multiple tympanostomy tubes. An audiogram confirmed a mild conductive hearing loss on the left and a maximum conductive hearing loss on the right. Otorhinolaryngology was asked to evaluate and manage his microtia and aural atresia. Recommendations were given to perform elective otoplasty with cartilage crafting as well as conchal setback. The middle son was diagnosed with Hartsfield syndrome on prenatal ultrasound. He was born at 39 4/7 weeks by vaginal delivery. At birth, he was identified to have low-set cupped-ears, auricular skin tags, severe bilateral cleft-lip and palate, nasal tip clefting, retrognathia and bilateral ectrodactyly of the hands and feet. Aerodigestive concerns were paramount, and initial attempts
J.D. Oliver et al. / International Journal of Pediatric Otorhinolaryngology 98 (2017) 4e8
at oral feeding with a Haberman feeder were unsuccessful; orogastric feeds were supplemented. A vinyl polysiloxane palatal obturator made by a prosthodonthist was placed to facilitate oral feeding. Early gastrostomy tube was placed at seventeen days of to facilitate nutrition and electrolyte balance per multidisciplinary recommendations of the otorhinolaryngology and endocrinology teams. Pre-surgical infant orthopedics of the bilateral cleft-lip was then completed with passive technique and taping of the upper lip. It should be noted that nasoalveolar molding (NAM) was attempted but not tolerated by this medically complex child. Bilateral cleft-lip was repaired at 10 weeks and the patient was discharged when medically stable. At seven months of age, tympanostomy tubes were placed to treat bilateral middle ear effusions and a moderate conductive hearing loss. The child's comorbidities included holoprosencephaly, diabetes insipidus, micropenis and mild juxtaductal coarctation of the aorta with care provided by General Surgery, Cardiothoracic Surgery, Endocrinology, and Neurology for multidisciplinary management. At ten days of age the patient underwent repair of coarctation of the aorta and extended end-to-end anastomosis with ligation of the ductus arteriosus. Unfortunately, at 18 months of age, he passed away, due to an upper respiratory illness associated with metabolic derangements and suspected cardiopulmonary event. The youngest sibling, also diagnosed in utero, presented at birth with hypertelorism, retrognathia, bilateral cleft-lip and palate, nasal clefting, nasal glioma, cupped-ear deformity and ectrodactyly. Similarly as the case above, a pre-emptive gastrostomy tube was placed at 2 weeks of age. He then underwent simultaneous cleft lip repair and nasal glioma excision at 10 weeks of age. Unfortunately, he was lost to follow-up for a short period of time after his sibling passed away, and his secondary craniofacial repairs were delayed. Cleft-palate repair with simultaneous bilateral myringotomy with tympanostomy tube placement then occurred at two years of age, accompanied by closely monitored electrolyte levels perioperatively. His post-operative course was complicated by palate repair dehiscence, gastrostomy tube feeding intolerance and electrolyte abnormalities. An effort to salvage the palate repair with re-repair was performed using permanent sutures and hyperbaric oxygen therapy, but was unsuccessful. His comorbidities include semilobar holoprosencephaly, diabetes insipidus and coarctation of the aorta. Endocrinology closely monitors his electrolyte balance, while Neurology accompanies his progress peripherally. He remains stable and closely monitored with plans to revise the cleft-palate. In summary, the characteristic phenotypic findings appreciated
5
in the family reported are listed in Table 1 and seen in Fig. 1 (see Table 2). 3. Discussion Hartsfield syndrome includes holoprosencephaly (HPE), ectrodactyly, and bilateral cleft lip-palate syndrome. The first case was described by Dr. J.K. Hartsfield, Jr. in 1984 [3], and there have been fewer than 20 cases reported in the literature to date. It is important to recognize this distinct syndrome in the otorhinolaryngology literature. Hartsfield syndrome features of cleft lip-palate and HPE syndromes are similar to important developmental syndromes, including Smith-Lemli-Opitz syndrome (SLOS), Pallister-Hall syndrome, as well as the group of p63-related disorders such as ectrodactylyeectodermal dysplasia-clefting (EEC) syndrome and Hay Wells (AEC) syndrome, and facial clefts and brachial amelia. However, Hartsfield syndrome has unique characteristics helping to uniquely define this syndrome. The cases were reported in this series, in an attempt to further define characteristics of this population and to improve in the future cares of these complex patients as more is identified about this complex disease process. The family reported in this case series has four male siblings, three of which harbor the FGFR1 variant c.1880G > C(p.Arg627Thr) and are affected by the disease. Interestingly, the patients' father was identified to have gonosomal mosaicism for this variant in sperm but not in blood or saliva and his sons display the complete genetic genotype [2]. No one in their family displayed effects of or was previously diagnosed with this condition. There are few cases scattered in the literature describing other associated genetic anomalies. However, the otorhinolaryngologic manifestations and implications of Hartsfield syndrome have not been reported previously. These findings are evolving, but as currently known a summary of the reported genetic and phenotypic findings has been included in Fig. 1. 4. Diagnosis and management 4.1. In-utero diagnosis Prenatal ultrasonography should be utilized to detect the presence of holoprosencephaly, ectrodactyly, and cleft-lip and palate in the affected fetus [2]. This diagnostic method was successfully used to detect these signs of Hartsfield syndrome in the youngest sibling in this case series. Several previously-reported cases of suspected
Table 1 Summary of otorhinolaryngologic findings in all three siblings. Patient Sex, DOB
Ectrodactyly
Cleft-lip & palate
Facial dysmorphism
Ear anomalies
M, 7/31/2007
Bilateral hand and foot
Bilateral Cleft lip Cleft palate
M, 8/13/2014
Bilateral hand and foot
Bilateral Cleft lip Cleft palate
M, 2/11/2015(deceased)
Bilateral hand and foot
Bilateral Cleft lip Cleft palate
Hypertelorism Bilateral epicanthal folds Malar and midface hypoplasia Nasal tip clefting Central incisor Retrognathia Hypertelorism Bilateral epicanthal folds Malar and midface hypoplasia Nasal glioma Nasal tip clefting Retrognathia Hypertelorism Bilateral epicanthal folds Malar and midface hypoplasia Nasal tip clefting Retrognathia Glossoptosis
Low-set ears Bilateral microtia Unilateral aural atresia Cupped-ear deformity Auricular skin tag Auricular pit Low-set ears Cupped-ear deformity
Low-set ears Cupped-ear deformity Auricular skin tag
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Table 2 Summary of all patients in the literature with Hartsfield syndrome documented to date identifying sex, country or origin and genetic anomalies [1,2,4e10]. Key: FGFR1eFibroblast Growth Factor Receptor 1; SHH e Sonic Hedgehog; SIX3 - SIX Homeobox 3; ZIC2 - Zinc finger of the cerebellum (ZIC) protein 2; TGIF - TGFB-induced factor; FISH e Fluorescence in situ hybridization; TP63 - transformation-related protein 63; GLI2 - GLI Family Zinc Finger 2; SLC25A43 - Solute Carrier Family 25 Member 43; SLC25A5eSolute Carrier Family 25 Member 5; CXorf56 - Chromosome X Open Reading Frame 56; UBE2A - Ubiquitin Conjugating Enzyme E2 A; KAL1 - Kallmann syndrome 1 sequence. Patient sex, age at diagnosis
Author
Country
Genetic testing/Mutations
Clinical anomalies
M, 5 years
Dhamija et al 2014 Dhamija et al 2014 Dhamija et al 2014 El Hawrani et al 2005 Kalil and Fargalley 2012 Keaton et al 2010 Keaton et al 2010 Keaton et al 2010 Vilain et al 2009
USA
FGFR1
USA
FGFR1
USA
FGFR1
Canada
Not Known
Ectrodactyly, bilateral cleft lip and cleft palate, hypertelorism, retrognathia, bilateral microtia Ectrodactyly, bilateral cleft lip and cleft palate, hypertelorism, retrognathia, low-set ears Ectrodactyly, bilateral cleft lip and cleft palate, hypertelorism, retrognathia, low-set ears Hypotelorbitism, midline cleft lip, midline facial dysplasia
Egypt
Not Known
USA
No mutations in SHH,SIX3, ZIC2, or TGIF
USA
Not Known
Ectrodactyly, unilateral (right) cleft lip and cleft palate, dry rough skin with sparse, hypopigmented hair Ectrodacyly, bilateral cleft lip and palate, hypertelorsim, bilateral microtia, micropenis Ectrodactyly, midline cleft lip and palate
USA
Normal FISH for 7q21.3. No mutations in TP63
Ectrodactyly, hypotelorism, right ear overfolded
Belgium
Not Known
Ectrodactyly, unilateral (left) cleft lip and cleft palate, hypertelorism, right ear malformation Ectrodactyly, micropenis, cryptorchidism Ectrodactyly, bilateral cleft lip and palate, hypertelorism left preauricular skin tag, small external genitalia Ectrodactyly, midline cleft lip and cleft palate, hypotelorism, low-set ears Ectrodactyly, bilateral cleft lip and cleft palate, hypertelorism, left pre-auricular skin tag, small external genitalia, Ectrodactyly of the hands only, bilateral cleft lip and cleft palate, depressed nasal bridge, micropenis Facial dysmorphism, ectrodactyly, profound left-sided hypoacusis, micropenis Ectrodactyly, bilateral cleft lip and cleft palate, right-sided microtia
M, at birth M, at birth M, 4 months F, 11 months M, 2 years F, 24 weeks gestation F, not reported M, 24 weeks gestation M, 2 years M, at birth
Vilain et al 2009 Belgium Vilain et al 2009 Belgium
No GLI2 or TP63mutations. No GLI2 or TP63mutations.
M, at birth
Vilain et al 2009 Belgium
No GLI2 or TP63mutations.
M, at birth
Vilain et al 2009 Belgium
No GLI2 or TP63mutations.
M, at birth
Takenouchi et al Japan 2012 skaSowin Poland Seidler et al 2014 Prasad et al 2016 United Kingdom Hartsfield et al USA 1984
210 kb duplication of Xq24, involving genes SLC25A43, SLC25A5, CXorf56, and UBE2A Duplication of 110,967 bp onXp22.31, KAL1 overexpression p.Asn628Ser, impairment of FGFR1 kinase activity
M, 12 years M, at birth M, at birth
Not Known
Hartsfield syndrome have emphasized the usefulness of fetal brain imaging in the differential diagnosis of syndromal-clefting diagnosed in-utero, particularly when ectrodactylyeectodermal dysplasia-clefting syndrome is suspected [4]. Additionally, previous prenatal ultrasonography studies of affected fetuses have demonstrated measurements appropriate for gestational age, brain structures consistent with lobar holoprosencephaly, splaying of the cerebellar vermis, midline facial cleft, absence of a definitive nose, normal upper extremities, dysmorphic spine with hemivertebrae and several areas of lordosis and kyphosis extending from the cervical through lumbar regions. Normal external genitalia has been documented previously, however micropenis or underdevelopment of female genitalia has also been reported [5]. In the siblings included in this report, fetal echocardiogram has shown the presence of an interrupted aortic arch, coarctation of the aorta, and ventricular septal defects. 4.2. Otologic considerations It is recommended that routine newborn hearing screening be performed per state health guidelines with early referral to an Otolaryngologist when the diagnosis of Hartsfield syndrome is made. For the Otorhinolaryngologist, if aural atresia is present, consider an aural rehabilitation device such as a bone-conduction hearing device or BiCros hearing aid by three months of age. For microtia spectrum, six years old is the accepted age at which to perform reconstruction [6]. Likewise, patients with Hartsfield syndrome display various degrees of microtia and cupped-ear
Ectrodactyly, unilateral (right) cleft lip and cleft palate, hypertelorism, low-set ears
deformity. However, repair is elective, and should be performed only if the patient is medically stable. In particular with this syndrome, electrolyte management should take precedence. Consideration should also be made for tympanostomy tube placement, based on chronic otitis media with effusion, an essentially universal finding seen in our patients. The aforementioned otologic abnormalities may result in varying degrees of conductive hearing loss. No vestibulocochlear anomalies have been identified in those affected with Hartsfield syndrome, thus routine imaging for these types of anomalies is likely unnecessary although are likely obtained regardless in the setting of microtia. Sensorineural hearing loss has not been reported. 4.3. Cleft-lip and palate management In Hartsfield syndrome, the degree of clefting is severe, and consequently, columellar length in this patient population is drastically shortened to the point of near agenesis, which makes for particularly difficult cleft-lip nasal repair. Primary cleft-lip repair may be undertaken within the normal 10 week window provided the patient is medically stable. Recommended pre-operative consults include Endocrinology, Nutrition, and Airway Management, to ensure the patient can tolerate the procedure. Pre-surgical infant orthopedics, including passive taping and obturator placement with or without nasoalveolar molding may be attempted prior to cleft-lip and palate repair. Bilateral straight line closure technique was employed for a “cut-as-you-go”, tissue-sparing approach. Consideration must be paid to the large premaxillary segment
J.D. Oliver et al. / International Journal of Pediatric Otorhinolaryngology 98 (2017) 4e8
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Fig. 1. Image panel of three siblings presenting with Hartsfield syndrome. 1a - Grade 3 microtia (top left); 1b - Aural atresia (top middle); 1c - Cupped-ear deformity (top right); 2a - Bilateral cleft lip with dynacleft tape (middle left); 2b - Obturator placement and nasal clefting (middle middle); 2c - Nasal glioma (middle right); 3a,b - Ectrodactyly hands (bottom left and middle); 3c - Ectrodactyly foot (bottom right).
protrusion which makes primary orbicularis oris repair challenging. Severe hypolasia of the nasal tip cartilages should be addressed by utilizing primary rhinoplasty techniques at time of cleft-lip repair. Single dome and intradomal sutures may be performed at time of cleft-lip repair to improve nasal tip clefting and tip position. It is important to be aware of poor wound healing in the premaxillary segment in these patients. Minimalistic dissection is encouraged. Delayed palate repair is recommended to allow for growth prior to reconstruction. In our experience, clefting seen in this patient population is extremely wide and subject to high-tension closures. In performing cleft-palate repair, a two-flap palatoplasty approach
was taken utilizing bilateral vomer flaps. A nasoalveolar molding or a latham appliance is therefore helpful if tolerated. 4.4. Aerodigestive considerations Clinical presentation of the bilateral cleft-lip and palate with retrognathia in Hartsfield syndrome should alert the clinician to aspiration and obstruction risks. Oral and nasal airway may be difficult to use in these patients secondary to severe cleft-lip and palate. However, with orthopedic appliances in place they may still be safely attempted. Tongue-lip adhesion or tracheostomy could be
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considered to facilitate airway patency, although no patient in this series required it. Similarly, we have not identified obstructive sleep apnea as a significant comorbiditiy in the cases presented here, nor in literature review. Difficulty coordinating suck-and-swallow secondary to central delays and severe clefting is seen in Hartsfield syndrome. Palatal obturator placement can facilitate nasogastric tube placement while oral feeds are attempted with a specialized cleft-feeder. However, ultimately, strong consideration should be given to early gastrostomy tube placement, not only to facilitate feeding but to help manage extreme electrolyte disturbances often seen with systemic illness and dehydration in these patients perioperatively. Routine microdirect laryngoscopy can be performed at the time of cleft-lip repair or cleft-palate repair, if the procedure is indicated.
were referred to Cardiothoracic Surgery for repair without complication.
4.5. Endocrinologic considerations
Financial disclosures
Those affected with Hartsfield syndrome are at risk for central diabetes insipidus, hypogonadotropic hypogonadism, and other dysfunction of the hypothalamic pituitary axis. From an endocrinologic standpoint, this syndrome is often characterized by these abnormalities. Given the potential severity of these endocrinologic dysfunctions, daily follow-up by Endocrinology is recommended to ensure continued monitoring of the urine output as well as a serum sodium and simultaneous serum and urine osmolality. To better assess the rest of the hypothalamic pituitary axis, it is recommended to measure free T4, TSH, LH, FSH, testosterone, and random growth hormone levels. If the patient does have increasing sodium or increasing urine output, in particular exceeding 5 mL/kg per hour, it is recommended to initiate desmopressin treatment. Desmopressin can be administered by a variety of routes including subcutaneous, nasal, or oral to control central diabetes insipidus. 4.6. Multidisciplinary care Multidisciplinary management of pertinent symptoms is fundamental to the successful treatment of Hartsfield syndrome. Clinical geneticists provide diagnostic evaluations and genetic testing to identify the underlying cause of the condition. Genetic counseling provides understanding of the mechanism of inheritance and the chance for familial recurrence. While most patients have autosomal dominant inheritance and a de novo mechanism is implied, gonosomal mosaicism, which in this case was paternal, can be the source of recurrence [2]. Although not highlighted here, a plastic surgeon may be involved in the craniofacial repair and/or the management of ectrodactyly. Prosthodontics, General Surgery, and speech and swallow specialists will be crucial in aiding in the mode of alimentation, setting the foundation for stable electrolyte measures. Similarly, Endocrinology is also crucial in the management of holoprosencephaly sequelae including diabetes insipidus. Two of our patients had confirmed cardiac defects, for which they
5. Conclusion Hartsfield syndrome is exceedingly rare, as evidenced by the limited number of documented cases to date. Accurate diagnosis of this disease can be achieved through prenatal ultrasound and through identification of post-natal holoprosencephaly, cleft-lip and palate and ectrodactyly. The Otolaryngologist's recognition of this condition as well as management of the bilateral cleft-lip and palate, retrognathia, nasal clefting, external ear anomalies, and eustachian tube dysfunction, is critical in the care of those affected by Hartsfield syndrome.
None. Acknowledgements We would like to thank Dr. Lisa Schimmenti for her help with the genetic analysis of this report. References [1] M. Kalil, K. Abbass, H.S. Fargalley, Holoprosencephaly in an Egyptian baby with ectrodactyly-ectodermal dysplasia-cleft syndrome: a case report, J. Med. Case Rep. 6 (2012) 35. [2] R. Dhamija, S. Kirmani, X. Wang, et al., Novel de novo heterozygous FGFR1 mutation in two siblings with hartsfield syndrome: a case of gonadal mosaicism, Am. J. Med. Genet. Part A 9 (2014) 2356e2359. [3] J.K. Hartsfield, D. Bixler, W.E. DeMeyer, Syndrome identification case report 119: hypertelorism associated with holoprosencephaly and ectrodactyly, Clin. Dysmorphol. 2 (1984) 27e31. [4] A. El-Hawrani, M. Sohn, M. Noga, H. El-Hakim, The face does predict the braindmidline facial and forebrain defects uncovered during the investigation of nasal obstruction and rhinorrhea: case report and a review of holoprosencephaly and its classifications, Int. J. Pediatr. Otorhinolaryngology 70 (2006) 935e940. [5] A.A. Keaton, B.D. Solomon, A.J. Van Essen, et al., Holoprosencephaly and ectrodactyly: report of three new patients and review of the literature, Am. J. Med. Genet. Seminars Med. Genet. 154C (2010) 170e175. [6] M. Abdel-Aziz, Congenital aural atresia, J. Craniofacial Surg. 24 (2013) 418e422. [7] C. Vilain, G. Mortier, G. Van Vliet, et al., Hartsfield holoprosencephalyectrodactyly syndrome in 5 male patients: further delineation and review, Am. J. Med. Genet. Part A 149 (2009) 1476e1481. [8] T. Takenouchi, H. Okuno, R. Kosaki, et al., Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting, Am. J. Med. Genet. Part A 158 (2012) 2537e2541. ska-Seidler, M. Piwecka, E. Olech, et al., Hyperosmia, ectrodactyly, [9] A. Sowin mild intellectual disability, and other defects in a male patient with an Xlinked partial microduplication and overexpression of the KAL1 gene, J. Appl. Genet. 56 (2014) 177e184. [10] R. Prasad, C. Brewer, C.P. Burren, Hartsfield syndrome associated with a novel heterozygous missense mutation in FGFR1 and incorporating tumoral calcinosis, Am. J. Med. Genet. Part A 170 (2016) 2222e2225.