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The Coffin-Lowry syndrome: An inherited faciodigital mental retardation syndrome
724
May 1975 The Journal o f P E D I A T R I C S
The Coffin-Lowry syndrome: An inherited f aciodigital mental retardation syndrome Eight patients in threefamilies had mental retardation, characterist&facies and hands, and skeletal changes; the clinical features suggested to us that they had a syndrome previously thought to represent two entities described by Lowry and associates I and by Coffin and associates, 2 respectively. New findings include skeletal, orodental, and dermatoglyphic abnormalities and histopathologic changes suggesting that the syndrome is a heritable disorder of connective tissue. Severe expression in males and transmission through mildly affected females suggest X-linked or sex-influenced autosomal dominant inheritance.
Samia A. Temtamy, M.D., Ph.D.,* J. Daniel Miller, M.D., and Irene Hussels-Maumenee, M.D.,** Baltimore, Md.
FOR PROPER GENETIC COUNSELING the clinical delineation of simply inherited mental retardation syndromes is essential. In the present study we describe the clinical and genetic characteristics of a syndrome, previously thought to represent two distinct entities. Lowry and associates 1described mental retardation in a family with ten affected individuals in three generations; both males and females had small stature, characteristic facies, and tapering fingers. Coffin and associates 2 described two unrelated mentally retarded males, who had coarse facies, large soft hands, small stature, and skeletal anomalies; female relatives had mild manifestations. Subsequent reports 3, 4 of the synFrom the Moore Clinic, Division o f Medical Genetics, Department of Medicine, Johns Hopkins Hospital *Supported by postdoctoral Fellowshipfrom the National Foundation-March of Dimes. Assistant Professorof Human Genetics, NationalResearch Center, Cairo, Egypt. **Supported by Research CareerDevelopment awardGM70124 from the National Institutes of Health, Education and Welfare; Grant-ln-Aidfrom Fightfor Sight, lnc.; a grantgiven to the Department of Medical Genetics, The Moore Clinic, by the National lnstitutes of Health: 5 PO1GM 19489--Study of Human Genetics, 5 TO1GM O0795--Medical Genetics Training Grant, and OPD-CRC, 1 MO1RROO722--Heritable Disorders of Connective Tissue and GeneticMarker Studies. Also given was a grant by the National Foundation-March of Dimes-CRBS-322.
Vol. 86, No. 5, pp. 72,t-731
dromes described by Coffin and associates 2emphasized the clinical features of the syndrome in males. In this communication we report a hereditary faciodigital syndrome. Mental retardation and skeletal involvement of varying degrees occurred and males were more severely affected than females. The clinical and genetic features in our patients suggest that the syndromes described by Coffin and associates 2 and by Lowry and associates I are one and the same. Abbreviation used EEG: electroencephalogram
J
New findings in the patients that we studied were in the mouth, teeth, skeleton, and dermatoglyphics. Clinical and histopathologic findings suggest that the CoffinLowry syndrome is a heritable disorder of connective tissue. S U B J E C T S AND M E T H O D S Three unrelated white families were ascertained through three probands who were found to have the same faciodigital mental retardation syndrome. The pedigrees of these families are shown in Fig. 1. The proband of the M family (M.III-8) was mentally retarded and referred to us because of obesity and
Volume 86 Number 5
The Coffin-Lowry syndrome
I
The M Family
9
725
Affected, male & f e m a l e Probably affected i~liscarriage
IE
[]
i
Died in infancy
i
Dead Examined
re,l, i 6 1
2
3
45
7~8
9
1 The F Family t
112
TF
~L
1.,2#2
3
4
5
6
7
8
T~# P Family
/4~
2
Fig. 1. Pedigrees of three families affected with the Coffin- Lowry syndrome.
clumsy gait. She had abnormal facial features and large soft hands with tapering fingers. Her mother and half sister were similarly affected, and h e r half b r o t h e r (M.III-2) was severely affected and committed to a state institution. The proband in the F family was a boy with severe mental retardation; his half sister and mother were mildly affected. The maternal grandmother was said to have had large hands and varicose veins, and a maternal aunt was mentally retarded and institutionalized with the diagnosis of Down syndrome. While studying M.III-2, we diagnosed the proband of the P family (P.iI-1) who was hospitalized at the same time for investigation of mental retardation. No other m e m b e r s of the P family were affected. Investigations done on all affected m e m b e r s included skeletal roentgenograms, orthoroentgenograms of lower limbs, urinary screening f o r amino acids and muCopolysaccharides, serum thyroxine, complete blood
Table I. Analysis of craniofacial features in CoffinLowry syndrome (present study)
Finding present Square forehead with prominent outer lateral aspects Bitemporal narrowing Thickened supraorbital ridges and outer margins Thickened sagittal suture Thickened zygomatic arch Antimongoloid slant of eyes Hypertelorism Broad nasal bridge, thick nasal septum, and antiverted nostrils Thickened prominent lips with pouting lower lip Open mouth facies Thick prominent chin Prominent ears
Males Females (3 patients) (5 patients) 3 3
5 4
3 3 3 3 3
4 0 0 3 3
3
5
3 3 3 3
3 0 3 0
726
Temtamy, Miller, and Hussels-Maumenee
The Journal of Pediatrics May 1975
Fig. 2A. Facies of affected males. Upper left is M.III-2 at 23 years, lower left is F.IV-2 at 10 years, upper and lower right are P.II-1 at 10 years. Note coarse facial features as described in Table I.
Fig. 2B. Facies of affected females. Upper left is M.II-2 at 42 years, lower left is M.III-6 at 17 years, upper right is F.II-4 at 35 years and lower right is M.III-8 at 11 years. Note similarities to affected males but more variability.
c o u n t , and r o u t i n e b l o o d c h e m i s t r y . G - b a n d i n g o f chromosomes in cultured lymphocytes was done on all. Skin biopsy was done on MJII-2, and both skin and conjunctival biopsies on F.IV-2. Tissue sections were e x a m i n e d for h i s t o p a t h o l o g i c a n d h i s t o c h e m i c a l changes by both light and electron microscopy. Skin fibroblast cultures were scrutinized for biochemical abnormalities. Electroencephalograms and echoencephal o g r a m s were done on all affected patients. Dermatoglyphics were studied in affected patients and in all available family members.
hypercellularity of the subepithelial connective tissue (Fig. 5,a and b). Many of these cells were filled with small i n t r a c y t o p l a s m i c i n c l u s i o n s w h i c h a p p e a r e d e i t h e r as clear v a c u o l e s or as i n t e n s e l y o s m i o p h i l i c droplets. Histochemical stains showed the latter inclusions to be Sudanophilic. All other stains for acid muc o p o l y s a c c h a r i d e , lipid, a n d l y s 0 s o m a l h y d r o l y t i c enzymes were negative. By electron microscopy (Fig. 5,c), the intracytoplasmic inclusions appeared as singlemembrane-limited bodies (0.3-0.5 tz in diameter) with pleomorphic contents, predominantly fine fibrillogranular material, and intensely electron dense bodies, the latter corresponding to the Sudanophilic inclusions visible by light microscopy. No abnormal extracellular material was evident. Epithelial, vascular endothelial, and neural cells appeared ultrastructurally unaffected.
RESULTS Pertinent findings are shown in Figs. 2 to 4 and Tables I to III. Since the frequency and severity of the findings in affected subjects differed in the two sexes, the findings are listed s e p a r a t e l y . K a r y o t y p e s a n d biochemical studies were normal in all cases. By light microscopy, conjunctival and skin biopsy specimens from patient F. IV-2 demonstrated moderate
DISCUSSION Previous reports of Coffin syndrome 2-4 emphasized the manifestations in males. In the family reported by
Volume 86 Number 5
The Coffin-Lowry syndrome
727
Fig. 2C. Hands in three affected females F.III-4, M.II-2, and M.III-8, and one affected male M.III-2 (lower right). Lowry and associates 1both males and females were affected. The findings in the proposita and other affected females in that family* were similar to those in affected females that we studied. Since X-linked inheritance of Coffin syndrome was previously suspected by Procopis and Turner, 4 one of our main objectives was the proper delineation of the syndrome in females. The main features of the syndrome, which were more marked in males and progressive with age, will be discussed separately. Facial features. The facies in the Coffin-Lowry syndrome, combined with developmental retardation, led in the past to the misdiagnosis of Down syndrome, cretinism, or idiopathic hypercalcemia. Progressive coarsening of facial features and the appearance of skeletal changes suggested the diagnoses of m u c o p o l y s a c charidoses or of acromegaly in later childhood and in adults. Whereas the facial features were characteristic in males, the variability of features in females sometimes overlapped with normal. Hand changes, Although variability occurred, the appearance of the hands (broad, thick, hyperextensible fingers which tapered distally) was probably diagnostic. Nenrologie manifestations. Mental retardation was severe in all affected males, and variable in affected females. Our patients had progressive deterioration of" mental faculties. Internal communicating hydrocephalus has been previously noted. 1, 2 Large anterior fon*Dr. Lowry kindlyprovidedus with photographsof the handsof his patients.
Fig. 3. Clinical evidence of connective tissue disorder. Upper left shows kyphosis in M.III-6 at age 17 years. Upper middle shows severe scoliosis in M.III-2 at age 23 years. Upper right shows pectus carinatum in F.IV-2 at age 10 years. Lower right shows pectus excavatum in P.II-t at age 10 years. Lower left shows hyperextensible hand joints and fiat feet as seen in all affected individuals.
728
Temtamy, Miller, and Hussels-Maumenee
The Journal of Pediatrics May1975
Table II. Analysis of roentgenologic changes in CoffinLowry syndrome (present study)
Fig. 4A. Radiographic changes in Coffin-Lowry syndrome. Skull. Upper and lower left are skull of M.III-2, a male, showing hypertelorism; thickened calvaria, outer orbital walls, and orbital roofs; and localized hyperostoSis in frontal region (lateral view). Upper and lower right are skull of a female, M.III-6, showing similar but less marked changes and enlarged frontal sinuses. tanelle and delayed midline ossification were observed in two of the males studied by us (M.III-2 and F.IV-2). Early medical records were available for these two males only. Echoencephalograms in four of our patients (M.II-2, M.III-8, F.IV-2, and P.II-1) showed mild dilatation of the lateral ventricles. While minor electroencephalographic abnormalities were present in two affected females in our Study (M.II-2 and M.III-8), seizure discharges occurred in the E E G of only one affected male (P.II-1). Electroencephalographic abnormalities and epilepsy have been noted in other patientsJ Hyperreflexia of both legs, right footdrop, and ankle clonus noted in F.IV-2, which was not noted three years earlier, may indicate progressive motor deterioration similar to that noted in previously reported affected malesY 4 Skeletal changes. Sternal malformations were present at birth in two males studied by us (F.IV-2 and P.II-1) and in previously reported patients. 2, 4 Mild sternal malformations were noted in two females (F.VI-1 and M.III-6). Kyphosis and scoliosis, probably due to associated
Skull Hypertelorism Thickened facial bones HyperostosiS frontalis interna Spine Kyphoscoliosis Discogenic disease Narrowed intervertebral spaces Hands Short distal phalanges with prominent tufting Lack of modeling of bases of middle phalanges Short other phalanges/metacarpals Retarded bone age Sternum Pectus carinatum/excavatum Bifid lower end Lower limbs Narrow iliac wings Short wide femoral necks and coxa valga Lower limb length discrepancy Short great toe
Males ('present/ total)
Females (present/ total)
3/3 2/3 3/3
3/5 3/5 4/5
3/3 2/3 3/3
3/5 0/5 3/5
3/3
4/5
3/3
5/5
2/3 2/2
2/5 3/3
2/3 1/3
1/5 1/5
3/3 1/3
4/5 2/5
1/3 2/3
3/5 3/5
ligamentous laxity and changes in intervertebral discs, were only mild in females. Whereas hypertelorism was seen in all males it was present in only three of the five affected females studied by us. Thickening of the calvarium and internal hyperostosis were seen in both sexes, suggesting a small size of the brain. Although two pre',(iously reported males had head circumferences at or below the third percentile ~, 2 the head circumferences in our patients varied between the tenth and fiftieth percentile. The skeletal changes in our patients, which have not been described in detail by previous authors, include n a r r o w iliac wings; nonspecific s h o r t e n i n g o f long bones of the legs and of the metacarpals, great toe, and phalanges; short and wide femoral necks, coxa valga. Unequal length of the legs was a factor in the waddling, clumsy gait. Reduced stature in males and females and obesity in females, noted by other investigators 1"4 were also present in our patients. Orodental findings, Previous reports of Coffin-Lowry syndrome 1-4mentioned orodental changes which, however, were not completely investigated. All of our pa-
Volume 86 Number 5
tients had thick lips with pouting lower lip. Malocclusion with anterior overjet or open bite or both was f o u n d in five of six of our patients. Partially cleft tongue, manifest as a deep midline furrow of the dorsal surface of the whole body of the tongue, was present in all of our patients and was associated with ankyloglossia in one case (P.II-1) and with hypertrophic lingual frenulum in another (M.III-8). P.II-1 had unilateral repaired cleft lip. We observed bilateral winging of the upper central incisors associated with diastema and pegged lateral incisors in two unrelated patients (M.III-8 and F.IV-2) who also had protruding upper central incisors and poor alignment of upper anterior teeth. Each of the three unrelated affected males had congenital absence of one or two lower central incisors. Four of our patients had multiple hypodontia. All of our patients had torus palatinus of different types and degrees. Though a partial midline furrow of the tongue is common in the general population,5 a complete furrow, as noted in our patients, is rare. Most of the above mentioned orodental findings are rather c o m m o n in general population,6, 7 but some of these changes, particularly multiple hypodontia and the incisor anomalies, may be part of the Coffin-Lowry syndrome. D e r m a t o g l y p h i c changes. T h e most c o n s t a n t dermatoglyphic change in our patients was a transverse hypothenar crease, a finding that was emphasized by previous investigators,2, 4 and may be diagnostic. The increase in the atd angle previously described2, 4 was also present in our cases. Coffin and associates 2 found a single transverse crease in their two probands, but five of eight patients had Sydney lines. Sydney line was a familial trait in the M family. Significant dermatoglyphic changes, not previously reported, were an increased of interdigital patterns, an increase of a-b ridge count, and a low total ridge cOunt. The two patients studied by Coffin and associates 2 had a low total ridge count. Evidence of a connective tissue disorder. The skin in males is loose and easily stretched. Inguinal hernias were present in two of our patients, and in a previous case: 1The feet were fiat in all patients.2 Case " A " studied by Coffin and associates 2 had rectal prolapse and M.II-2 of our study had an advanced degree of uterine prolapse that n e c e s s i t a t e d h y s t e r e c t o m y . The veins were dilated and easily seen and there were fine capillary telangiectasiae in the three affected males, and extensive varicose veins of the legs in the two affected mothers whom we studied. Cutis marmorata and discoloration of the hands and feet, when held dependent, were present in both sexes. There was clinical evidence of mitral regurgitation in M.III-2. The hair was straight
The Coffin-Lowry syndrome
729
Fig. 4B. Radiographic changes in Coffin-Lowry syndrome. Upper left is hand showing short distal phalanges with prominent tufting and lack of modeling of bases of middle phalanges. Lower left is pelvis of F.III-4 showing narrowed iliac wings, short and wide femoral necks, and irregular ossification of the proximal femoral metaphyses. Upper right is lumbosacral region of spine of F.III-4, age 10 years, showing concavity of the superior and inferior surfaces of many vertebral bodies, irregularities of superior end plates, and sclerosis and narrowed interveterbral discs. Lower right is lumbosacral spine of M.III-2 showing scoliosis and considerable narrowing of the discs between Tll , Tl2, and L2. and coarse in all affected males. All of these findings suggested that the Coffin-Lowry sYndrome is a heritable disorder of connective tissue. Coffin and associates 2 found a greatly reduced n u m b e r of elastic fibrils in skin and subcutaneous tissue and an abnormal arrangement of chondrocytes in the probands. No histologic abnormalities of the skin were found by Procopis and Turner 4 or in our patients. The histopathologic changes in our patient F.IV-2, on whom results are available, suggest that the Coffin-Lowry syndrome is a lysosomal storage disorder. Studies on other patients are still in progress. Genetics. The total n u m b e r of well-documented reported cases of the Coffin-Lowry syndrome, including our own patients, is now 28 (12 males and 16 females) in eight families. The patient of Martinelli and Campallia3and our patient P.II-1 are sporadic. In the familial cases, the trait is transmitted in a vertical pedigree pattern, so far, without male-to-male transmission. None of the affected males, however, have reproduced, so
730
Temtamy, Miller, and Hussels-Maumenee
The Journal of Pediatrics May 1975
Fig. 5. Histopathologic findings in FJV-2. A, Light photomicrograph of conjunctiva showing increased cellularity of subepithelial connective tissue. Fibrocytic cells contain clear vacuoles (circled) and dense inclusions (arrowheads). (E, Epithelium; phase contrast, paraphenylenediamine; x 1,100). B, Light photomicrograph of skin illustrates connective tissue cells of dermis with both clear (circled) and dense (arrowheads) inclusions. (E, Epidermis; phase contrast, paraphenylenediemine, • 1,100). C, By electron microscopy, a conjunctival connective tissue cell is shown to contain numerous single-membrane-limitedinclusions with either fine granular (*) or electron-dense, globular (arrowheads) contents. (N, Nucleus; C, collagen; • Table III. Comparison of main findings in Coffin-Lowry syndrome in previously reported patients and the present study
Previously reportedcases
Present study
Total
I"
Abnormafity Characteristic facies Severe mental retardation (IQ 50 or less) Mild/moderate mental retardation Reduced stature Hand changes Sternal malformations Vertebral changes Cranial changes
Males Females Males Females Males Females (present~total) (present~total) (present~total) (present~total) (present~total) (present~total) 9/9 8/8 0/8 8/8 9/9 6/9 6/8 8/8
male-to-male transmission, which could rule out Xlinked inheritance, could not be excluded. The findings that males are consistently more severely affected than females and that manifestations in females are more variable, suggest X - l i n k e d i n h e r i t a n c e . A u t o s o m a l d o m i n a n t sex-influenced inheritance could not be ex-
9/11 1/11 8/11 7/11 9/11 1/11 ? 1/1
3/3 3/3 0/3 3/3 3/3 2/3 3/3 2/3
3/5 2/5 3/5 4/5 5/5 1/5 3/5 3/5
12/12 11/11 0111 11/ 11 12/12 8/12 9/11 10/11
12/16 3/16 l 1f16 11/ 16 14/16 2/16 3/5 4/6
cluded. In two of our families multiple spontaneous a b o r t i o n s o c c u r r e d in two affected females. I n our families (Fig. 1) and in previously reported families there were multiple abortions and deaths early in life, particularly in males J, 4 These findings suggest that the trait may be lethal in severely affected patients.
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The facial features, severe mental retardation, and skeletal changes are conspicuous in affected males; in affected females, in w h o m m a n i f e s t a t i o n s are more variable and sometimes overlap with normal, the diagnosis of Coffin-Lowry syndrome can be established by combined clinical and roentgenologic studies. Electron microscopic changes which are suggestive of a lysosomal storage disorder need to be confirmed by study of additional examples of the Coffin-Lowry syndrome.
We wish to thank Drs. John P. Dorst, Carlos Salinas, and Yves Lacassie for their assistance in the evaluation of the patients; Dr. R. K. Kenyon for the electron microscopic studies; and Dr. D. S. Borgaonkar for the chromosome studies. We gratefully acknowledge the continued encouragement of Drs. Victor A. McKusick and Edmond A. Murphy during various stages of this study.
The Coffin-Lowry syndrome
731
REFERENCES
1. Lowry B, Miller JR, and Fraser C: A new dominant gene mental retardation syndrome, Am J Dis Child 121:496, 1971. 2. Coffin GS, Siris E, and Wegienka LC: Mental retardation with osteocartilaginous anomalies, Am J Dis Child 112:205, 1966. 3. Martinelli B, and Campailla E: Contributo alia consoscenze della sindrome di Coffin, Siris, and Wegienka, G Psichiat Neuropat 97:449, 1969. 4, Procopis PG, and Turner B: Mental retardation, abnormal fingers, and skeletal anomalies. Coffin's syndromes, Am J Dis Child 124:258, 1972. 5. Shaefer W, Hine M, and Levy B: Oral pathology, Philadelphia, 1974, WB Saunders Company. 6. Meskin L, and Gorlin R: Agenesis and peg-shaped permanent maxillary lateral incisors, J Dent Res 42:1476, 1973. 7. Pindborg J J: Pathology of the dental hard tissues, Philadelphia, 1970, WB Saunders Company.
May 1975 The Journal o f P E D I A T R I C S
The Coffin-Lowry syndrome: An inherited f aciodigital mental retardation syndrome Eight patients in threefamilies had mental retardation, characterist&facies and hands, and skeletal changes; the clinical features suggested to us that they had a syndrome previously thought to represent two entities described by Lowry and associates I and by Coffin and associates, 2 respectively. New findings include skeletal, orodental, and dermatoglyphic abnormalities and histopathologic changes suggesting that the syndrome is a heritable disorder of connective tissue. Severe expression in males and transmission through mildly affected females suggest X-linked or sex-influenced autosomal dominant inheritance.
Samia A. Temtamy, M.D., Ph.D.,* J. Daniel Miller, M.D., and Irene Hussels-Maumenee, M.D.,** Baltimore, Md.
FOR PROPER GENETIC COUNSELING the clinical delineation of simply inherited mental retardation syndromes is essential. In the present study we describe the clinical and genetic characteristics of a syndrome, previously thought to represent two distinct entities. Lowry and associates 1described mental retardation in a family with ten affected individuals in three generations; both males and females had small stature, characteristic facies, and tapering fingers. Coffin and associates 2 described two unrelated mentally retarded males, who had coarse facies, large soft hands, small stature, and skeletal anomalies; female relatives had mild manifestations. Subsequent reports 3, 4 of the synFrom the Moore Clinic, Division o f Medical Genetics, Department of Medicine, Johns Hopkins Hospital *Supported by postdoctoral Fellowshipfrom the National Foundation-March of Dimes. Assistant Professorof Human Genetics, NationalResearch Center, Cairo, Egypt. **Supported by Research CareerDevelopment awardGM70124 from the National Institutes of Health, Education and Welfare; Grant-ln-Aidfrom Fightfor Sight, lnc.; a grantgiven to the Department of Medical Genetics, The Moore Clinic, by the National lnstitutes of Health: 5 PO1GM 19489--Study of Human Genetics, 5 TO1GM O0795--Medical Genetics Training Grant, and OPD-CRC, 1 MO1RROO722--Heritable Disorders of Connective Tissue and GeneticMarker Studies. Also given was a grant by the National Foundation-March of Dimes-CRBS-322.
Vol. 86, No. 5, pp. 72,t-731
dromes described by Coffin and associates 2emphasized the clinical features of the syndrome in males. In this communication we report a hereditary faciodigital syndrome. Mental retardation and skeletal involvement of varying degrees occurred and males were more severely affected than females. The clinical and genetic features in our patients suggest that the syndromes described by Coffin and associates 2 and by Lowry and associates I are one and the same. Abbreviation used EEG: electroencephalogram
J
New findings in the patients that we studied were in the mouth, teeth, skeleton, and dermatoglyphics. Clinical and histopathologic findings suggest that the CoffinLowry syndrome is a heritable disorder of connective tissue. S U B J E C T S AND M E T H O D S Three unrelated white families were ascertained through three probands who were found to have the same faciodigital mental retardation syndrome. The pedigrees of these families are shown in Fig. 1. The proband of the M family (M.III-8) was mentally retarded and referred to us because of obesity and
Volume 86 Number 5
The Coffin-Lowry syndrome
I
The M Family
9
725
Affected, male & f e m a l e Probably affected i~liscarriage
IE
[]
i
Died in infancy
i
Dead Examined
re,l, i 6 1
2
3
45
7~8
9
1 The F Family t
112
TF
~L
1.,2#2
3
4
5
6
7
8
T~# P Family
/4~
2
Fig. 1. Pedigrees of three families affected with the Coffin- Lowry syndrome.
clumsy gait. She had abnormal facial features and large soft hands with tapering fingers. Her mother and half sister were similarly affected, and h e r half b r o t h e r (M.III-2) was severely affected and committed to a state institution. The proband in the F family was a boy with severe mental retardation; his half sister and mother were mildly affected. The maternal grandmother was said to have had large hands and varicose veins, and a maternal aunt was mentally retarded and institutionalized with the diagnosis of Down syndrome. While studying M.III-2, we diagnosed the proband of the P family (P.iI-1) who was hospitalized at the same time for investigation of mental retardation. No other m e m b e r s of the P family were affected. Investigations done on all affected m e m b e r s included skeletal roentgenograms, orthoroentgenograms of lower limbs, urinary screening f o r amino acids and muCopolysaccharides, serum thyroxine, complete blood
Table I. Analysis of craniofacial features in CoffinLowry syndrome (present study)
Finding present Square forehead with prominent outer lateral aspects Bitemporal narrowing Thickened supraorbital ridges and outer margins Thickened sagittal suture Thickened zygomatic arch Antimongoloid slant of eyes Hypertelorism Broad nasal bridge, thick nasal septum, and antiverted nostrils Thickened prominent lips with pouting lower lip Open mouth facies Thick prominent chin Prominent ears
Males Females (3 patients) (5 patients) 3 3
5 4
3 3 3 3 3
4 0 0 3 3
3
5
3 3 3 3
3 0 3 0
726
Temtamy, Miller, and Hussels-Maumenee
The Journal of Pediatrics May 1975
Fig. 2A. Facies of affected males. Upper left is M.III-2 at 23 years, lower left is F.IV-2 at 10 years, upper and lower right are P.II-1 at 10 years. Note coarse facial features as described in Table I.
Fig. 2B. Facies of affected females. Upper left is M.II-2 at 42 years, lower left is M.III-6 at 17 years, upper right is F.II-4 at 35 years and lower right is M.III-8 at 11 years. Note similarities to affected males but more variability.
c o u n t , and r o u t i n e b l o o d c h e m i s t r y . G - b a n d i n g o f chromosomes in cultured lymphocytes was done on all. Skin biopsy was done on MJII-2, and both skin and conjunctival biopsies on F.IV-2. Tissue sections were e x a m i n e d for h i s t o p a t h o l o g i c a n d h i s t o c h e m i c a l changes by both light and electron microscopy. Skin fibroblast cultures were scrutinized for biochemical abnormalities. Electroencephalograms and echoencephal o g r a m s were done on all affected patients. Dermatoglyphics were studied in affected patients and in all available family members.
hypercellularity of the subepithelial connective tissue (Fig. 5,a and b). Many of these cells were filled with small i n t r a c y t o p l a s m i c i n c l u s i o n s w h i c h a p p e a r e d e i t h e r as clear v a c u o l e s or as i n t e n s e l y o s m i o p h i l i c droplets. Histochemical stains showed the latter inclusions to be Sudanophilic. All other stains for acid muc o p o l y s a c c h a r i d e , lipid, a n d l y s 0 s o m a l h y d r o l y t i c enzymes were negative. By electron microscopy (Fig. 5,c), the intracytoplasmic inclusions appeared as singlemembrane-limited bodies (0.3-0.5 tz in diameter) with pleomorphic contents, predominantly fine fibrillogranular material, and intensely electron dense bodies, the latter corresponding to the Sudanophilic inclusions visible by light microscopy. No abnormal extracellular material was evident. Epithelial, vascular endothelial, and neural cells appeared ultrastructurally unaffected.
RESULTS Pertinent findings are shown in Figs. 2 to 4 and Tables I to III. Since the frequency and severity of the findings in affected subjects differed in the two sexes, the findings are listed s e p a r a t e l y . K a r y o t y p e s a n d biochemical studies were normal in all cases. By light microscopy, conjunctival and skin biopsy specimens from patient F. IV-2 demonstrated moderate
DISCUSSION Previous reports of Coffin syndrome 2-4 emphasized the manifestations in males. In the family reported by
Volume 86 Number 5
The Coffin-Lowry syndrome
727
Fig. 2C. Hands in three affected females F.III-4, M.II-2, and M.III-8, and one affected male M.III-2 (lower right). Lowry and associates 1both males and females were affected. The findings in the proposita and other affected females in that family* were similar to those in affected females that we studied. Since X-linked inheritance of Coffin syndrome was previously suspected by Procopis and Turner, 4 one of our main objectives was the proper delineation of the syndrome in females. The main features of the syndrome, which were more marked in males and progressive with age, will be discussed separately. Facial features. The facies in the Coffin-Lowry syndrome, combined with developmental retardation, led in the past to the misdiagnosis of Down syndrome, cretinism, or idiopathic hypercalcemia. Progressive coarsening of facial features and the appearance of skeletal changes suggested the diagnoses of m u c o p o l y s a c charidoses or of acromegaly in later childhood and in adults. Whereas the facial features were characteristic in males, the variability of features in females sometimes overlapped with normal. Hand changes, Although variability occurred, the appearance of the hands (broad, thick, hyperextensible fingers which tapered distally) was probably diagnostic. Nenrologie manifestations. Mental retardation was severe in all affected males, and variable in affected females. Our patients had progressive deterioration of" mental faculties. Internal communicating hydrocephalus has been previously noted. 1, 2 Large anterior fon*Dr. Lowry kindlyprovidedus with photographsof the handsof his patients.
Fig. 3. Clinical evidence of connective tissue disorder. Upper left shows kyphosis in M.III-6 at age 17 years. Upper middle shows severe scoliosis in M.III-2 at age 23 years. Upper right shows pectus carinatum in F.IV-2 at age 10 years. Lower right shows pectus excavatum in P.II-t at age 10 years. Lower left shows hyperextensible hand joints and fiat feet as seen in all affected individuals.
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Table II. Analysis of roentgenologic changes in CoffinLowry syndrome (present study)
Fig. 4A. Radiographic changes in Coffin-Lowry syndrome. Skull. Upper and lower left are skull of M.III-2, a male, showing hypertelorism; thickened calvaria, outer orbital walls, and orbital roofs; and localized hyperostoSis in frontal region (lateral view). Upper and lower right are skull of a female, M.III-6, showing similar but less marked changes and enlarged frontal sinuses. tanelle and delayed midline ossification were observed in two of the males studied by us (M.III-2 and F.IV-2). Early medical records were available for these two males only. Echoencephalograms in four of our patients (M.II-2, M.III-8, F.IV-2, and P.II-1) showed mild dilatation of the lateral ventricles. While minor electroencephalographic abnormalities were present in two affected females in our Study (M.II-2 and M.III-8), seizure discharges occurred in the E E G of only one affected male (P.II-1). Electroencephalographic abnormalities and epilepsy have been noted in other patientsJ Hyperreflexia of both legs, right footdrop, and ankle clonus noted in F.IV-2, which was not noted three years earlier, may indicate progressive motor deterioration similar to that noted in previously reported affected malesY 4 Skeletal changes. Sternal malformations were present at birth in two males studied by us (F.IV-2 and P.II-1) and in previously reported patients. 2, 4 Mild sternal malformations were noted in two females (F.VI-1 and M.III-6). Kyphosis and scoliosis, probably due to associated
Skull Hypertelorism Thickened facial bones HyperostosiS frontalis interna Spine Kyphoscoliosis Discogenic disease Narrowed intervertebral spaces Hands Short distal phalanges with prominent tufting Lack of modeling of bases of middle phalanges Short other phalanges/metacarpals Retarded bone age Sternum Pectus carinatum/excavatum Bifid lower end Lower limbs Narrow iliac wings Short wide femoral necks and coxa valga Lower limb length discrepancy Short great toe
Males ('present/ total)
Females (present/ total)
3/3 2/3 3/3
3/5 3/5 4/5
3/3 2/3 3/3
3/5 0/5 3/5
3/3
4/5
3/3
5/5
2/3 2/2
2/5 3/3
2/3 1/3
1/5 1/5
3/3 1/3
4/5 2/5
1/3 2/3
3/5 3/5
ligamentous laxity and changes in intervertebral discs, were only mild in females. Whereas hypertelorism was seen in all males it was present in only three of the five affected females studied by us. Thickening of the calvarium and internal hyperostosis were seen in both sexes, suggesting a small size of the brain. Although two pre',(iously reported males had head circumferences at or below the third percentile ~, 2 the head circumferences in our patients varied between the tenth and fiftieth percentile. The skeletal changes in our patients, which have not been described in detail by previous authors, include n a r r o w iliac wings; nonspecific s h o r t e n i n g o f long bones of the legs and of the metacarpals, great toe, and phalanges; short and wide femoral necks, coxa valga. Unequal length of the legs was a factor in the waddling, clumsy gait. Reduced stature in males and females and obesity in females, noted by other investigators 1"4 were also present in our patients. Orodental findings, Previous reports of Coffin-Lowry syndrome 1-4mentioned orodental changes which, however, were not completely investigated. All of our pa-
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tients had thick lips with pouting lower lip. Malocclusion with anterior overjet or open bite or both was f o u n d in five of six of our patients. Partially cleft tongue, manifest as a deep midline furrow of the dorsal surface of the whole body of the tongue, was present in all of our patients and was associated with ankyloglossia in one case (P.II-1) and with hypertrophic lingual frenulum in another (M.III-8). P.II-1 had unilateral repaired cleft lip. We observed bilateral winging of the upper central incisors associated with diastema and pegged lateral incisors in two unrelated patients (M.III-8 and F.IV-2) who also had protruding upper central incisors and poor alignment of upper anterior teeth. Each of the three unrelated affected males had congenital absence of one or two lower central incisors. Four of our patients had multiple hypodontia. All of our patients had torus palatinus of different types and degrees. Though a partial midline furrow of the tongue is common in the general population,5 a complete furrow, as noted in our patients, is rare. Most of the above mentioned orodental findings are rather c o m m o n in general population,6, 7 but some of these changes, particularly multiple hypodontia and the incisor anomalies, may be part of the Coffin-Lowry syndrome. D e r m a t o g l y p h i c changes. T h e most c o n s t a n t dermatoglyphic change in our patients was a transverse hypothenar crease, a finding that was emphasized by previous investigators,2, 4 and may be diagnostic. The increase in the atd angle previously described2, 4 was also present in our cases. Coffin and associates 2 found a single transverse crease in their two probands, but five of eight patients had Sydney lines. Sydney line was a familial trait in the M family. Significant dermatoglyphic changes, not previously reported, were an increased of interdigital patterns, an increase of a-b ridge count, and a low total ridge cOunt. The two patients studied by Coffin and associates 2 had a low total ridge count. Evidence of a connective tissue disorder. The skin in males is loose and easily stretched. Inguinal hernias were present in two of our patients, and in a previous case: 1The feet were fiat in all patients.2 Case " A " studied by Coffin and associates 2 had rectal prolapse and M.II-2 of our study had an advanced degree of uterine prolapse that n e c e s s i t a t e d h y s t e r e c t o m y . The veins were dilated and easily seen and there were fine capillary telangiectasiae in the three affected males, and extensive varicose veins of the legs in the two affected mothers whom we studied. Cutis marmorata and discoloration of the hands and feet, when held dependent, were present in both sexes. There was clinical evidence of mitral regurgitation in M.III-2. The hair was straight
The Coffin-Lowry syndrome
729
Fig. 4B. Radiographic changes in Coffin-Lowry syndrome. Upper left is hand showing short distal phalanges with prominent tufting and lack of modeling of bases of middle phalanges. Lower left is pelvis of F.III-4 showing narrowed iliac wings, short and wide femoral necks, and irregular ossification of the proximal femoral metaphyses. Upper right is lumbosacral region of spine of F.III-4, age 10 years, showing concavity of the superior and inferior surfaces of many vertebral bodies, irregularities of superior end plates, and sclerosis and narrowed interveterbral discs. Lower right is lumbosacral spine of M.III-2 showing scoliosis and considerable narrowing of the discs between Tll , Tl2, and L2. and coarse in all affected males. All of these findings suggested that the Coffin-Lowry sYndrome is a heritable disorder of connective tissue. Coffin and associates 2 found a greatly reduced n u m b e r of elastic fibrils in skin and subcutaneous tissue and an abnormal arrangement of chondrocytes in the probands. No histologic abnormalities of the skin were found by Procopis and Turner 4 or in our patients. The histopathologic changes in our patient F.IV-2, on whom results are available, suggest that the Coffin-Lowry syndrome is a lysosomal storage disorder. Studies on other patients are still in progress. Genetics. The total n u m b e r of well-documented reported cases of the Coffin-Lowry syndrome, including our own patients, is now 28 (12 males and 16 females) in eight families. The patient of Martinelli and Campallia3and our patient P.II-1 are sporadic. In the familial cases, the trait is transmitted in a vertical pedigree pattern, so far, without male-to-male transmission. None of the affected males, however, have reproduced, so
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Fig. 5. Histopathologic findings in FJV-2. A, Light photomicrograph of conjunctiva showing increased cellularity of subepithelial connective tissue. Fibrocytic cells contain clear vacuoles (circled) and dense inclusions (arrowheads). (E, Epithelium; phase contrast, paraphenylenediamine; x 1,100). B, Light photomicrograph of skin illustrates connective tissue cells of dermis with both clear (circled) and dense (arrowheads) inclusions. (E, Epidermis; phase contrast, paraphenylenediemine, • 1,100). C, By electron microscopy, a conjunctival connective tissue cell is shown to contain numerous single-membrane-limitedinclusions with either fine granular (*) or electron-dense, globular (arrowheads) contents. (N, Nucleus; C, collagen; • Table III. Comparison of main findings in Coffin-Lowry syndrome in previously reported patients and the present study
Previously reportedcases
Present study
Total
I"
Abnormafity Characteristic facies Severe mental retardation (IQ 50 or less) Mild/moderate mental retardation Reduced stature Hand changes Sternal malformations Vertebral changes Cranial changes
Males Females Males Females Males Females (present~total) (present~total) (present~total) (present~total) (present~total) (present~total) 9/9 8/8 0/8 8/8 9/9 6/9 6/8 8/8
male-to-male transmission, which could rule out Xlinked inheritance, could not be excluded. The findings that males are consistently more severely affected than females and that manifestations in females are more variable, suggest X - l i n k e d i n h e r i t a n c e . A u t o s o m a l d o m i n a n t sex-influenced inheritance could not be ex-
9/11 1/11 8/11 7/11 9/11 1/11 ? 1/1
3/3 3/3 0/3 3/3 3/3 2/3 3/3 2/3
3/5 2/5 3/5 4/5 5/5 1/5 3/5 3/5
12/12 11/11 0111 11/ 11 12/12 8/12 9/11 10/11
12/16 3/16 l 1f16 11/ 16 14/16 2/16 3/5 4/6
cluded. In two of our families multiple spontaneous a b o r t i o n s o c c u r r e d in two affected females. I n our families (Fig. 1) and in previously reported families there were multiple abortions and deaths early in life, particularly in males J, 4 These findings suggest that the trait may be lethal in severely affected patients.
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The facial features, severe mental retardation, and skeletal changes are conspicuous in affected males; in affected females, in w h o m m a n i f e s t a t i o n s are more variable and sometimes overlap with normal, the diagnosis of Coffin-Lowry syndrome can be established by combined clinical and roentgenologic studies. Electron microscopic changes which are suggestive of a lysosomal storage disorder need to be confirmed by study of additional examples of the Coffin-Lowry syndrome.
We wish to thank Drs. John P. Dorst, Carlos Salinas, and Yves Lacassie for their assistance in the evaluation of the patients; Dr. R. K. Kenyon for the electron microscopic studies; and Dr. D. S. Borgaonkar for the chromosome studies. We gratefully acknowledge the continued encouragement of Drs. Victor A. McKusick and Edmond A. Murphy during various stages of this study.
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REFERENCES
1. Lowry B, Miller JR, and Fraser C: A new dominant gene mental retardation syndrome, Am J Dis Child 121:496, 1971. 2. Coffin GS, Siris E, and Wegienka LC: Mental retardation with osteocartilaginous anomalies, Am J Dis Child 112:205, 1966. 3. Martinelli B, and Campailla E: Contributo alia consoscenze della sindrome di Coffin, Siris, and Wegienka, G Psichiat Neuropat 97:449, 1969. 4, Procopis PG, and Turner B: Mental retardation, abnormal fingers, and skeletal anomalies. Coffin's syndromes, Am J Dis Child 124:258, 1972. 5. Shaefer W, Hine M, and Levy B: Oral pathology, Philadelphia, 1974, WB Saunders Company. 6. Meskin L, and Gorlin R: Agenesis and peg-shaped permanent maxillary lateral incisors, J Dent Res 42:1476, 1973. 7. Pindborg J J: Pathology of the dental hard tissues, Philadelphia, 1970, WB Saunders Company.