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Case Examples
CHAPTER 10
Case Examples MEAGAN B. FARMER, MS, CGC • NATHANIEL H. ROBIN, MD
SCENARIOS Case 1
A 4-year-old female is being treated for adrenocortical carcinoma. Her pedigree is included below (Fig. 10.1). • What is the differential based on the information provided? • What, if any, testing would you begin with? • If the most likely condition is confirmed, what management recommendations would you make for this patient and her family?
Case 2 A 9-year-old boy presents with significant rectal bleeding and associated anemia. He is found to have six hamartomatous colorectal polyps on colonoscopy. His physical examination is negative. His pedigree is included below (Fig. 10.2). • What is the differential based on the information provided? • What, if any, further assessment and/or testing would you begin with? • If the most likely condition is confirmed, what management recommendations would you make for this patient and his family?
Case 3 A 6-week-old female presented with signs of impaired intestinal motility, including failure to pass meconium, constipation, and abdominal distention. Hirschsprung disease was confirmed with suction biopsies of the rectal mucosa and submucosa. A genetics consult was requested, and her physical examination was otherwise negative. Her parents were both present, and no dysmorphic features were noted. Her pedigree is below (Fig. 10.3). • What are the potential etiologies to consider for Hirschsprung disease?4 • What should the work-up include?4 • If the most likely condition is confirmed, what management recommendations would you make for the patient and her family?
Case 4 An 8-year-old male presents with pervasive developmental disorder not otherwise specified (autism).
His medical history is otherwise unremarkable. His pedigree is included below (Fig. 10.4). Chromosomal microarray and Fragile X testing were ordered by his pediatrician and were negative. Physical examination is only remarkable for macrocephaly (57 cm). • What should the genetics work-up of autism include? • Consider this case according to the proposed framework for evaluation. • If the most likely condition is confirmed, what management recommendations would you make for the patient and his family?
SOLUTIONS Case 1 A 4-year-old female is being treated for adrenocortical carcinoma. Her pedigree is included below (Fig. 10.1). • What is the differential based on the information provided? • Li-Fraumeni syndrome (adrenocortical carcinoma, breast cancer)1 • Beckwith-Wiedemann syndrome (adrenocortical carcinoma)1 • BRCA-related hereditary breast and ovarian cancer (breast cancer)2 • What, if any, testing would you begin with? • Both adrenocortical carcinoma and early-onset breast cancer are associated with Li-Fraumeni syndrome.1 Given this, TP53 sequencing and deletion/duplication analysis should be performed. • If the most likely condition is confirmed, what management recommendations would you make for this patient and her family? • See Li-Fraumeni management recommendations in Chapter 6. • Neither parent has a personal history of cancer, but a TP53 mutation could have been inherited from either parent or be de novo. Parents should be offered testing, beginning with her father given the paternal grandmother’s history of early-onset breast cancer. 115
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32 Br 29
33
31
53
51
Legend Ad - Adrenal cancer Br - Breast cancer
27
30
25
4 Ad 4 Case 1 Pt FIG. 10.1 A 4-year-old female being treated for adrenocortical carcinoma.
Legend 65
Polyp-Ham - Colon polyp
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60
62 Lun 61
Lun - Lung cancer
43
41
39
40
2 9 7 Polyp-Ham 9 Case 2 Pt FIG. 10.2 A 9-year-old boy presents with significant rectal bleeding and associated anemia.
CHAPTER 10 Case Examples
Legend
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22
34
32 ThyM 30
56
29
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55
27
25
Hirschsprung Dz ThyM - Thyroid cancer
5
6w 2 Hirschsprung Dz Case 3 Pt FIG. 10.3 A 6-week-old female presented with signs of impaired intestinal motility, including failure to pass meconium, constipation, and abdominal distention.
Case 2 A 9-year-old boy presents with significant rectal bleeding and associated anemia. He is found to have six hamartomatous colorectal polyps on colonoscopy. His physical examination is negative. His pedigree is included below (Fig. 10.2). • What is the differential based on the information provided? • Juvenile polyposis syndrome (hamartomatous polyps with anemia)3 • Cowden syndrome/PTEN hamartoma syndrome (hamartomatous polyps)3 • Peutz-Jeghers syndrome (hamartomatous polyps)3 • What, if any, further assessment and/or testing would you begin with? • Review of colon polyp pathology to determine whether polyps appear to be juvenile type • If he has more than five juvenile-type polyps of the colorectum, he meets clinical diagnostic criteria for juvenile polyposis syndrome (see JPS section within Chapter 7 for more information). • Physical examination was reportedly negative. Confirm that head circumference is within normal limits and that there are no mucocutaneous findings suggestive of Peutz-Jeghers syndrome
to reduce suspicion for Cowden syndrome and Peutz-Jeghers syndrome, respectively. • If the above assessment confirms suspicion of juvenile polyposis syndrome, perform BMPR1A and SMAD4 sequencing and deletion/duplication analysis. If a multigene panel, including analysis of several genes implicated in susceptibility to polyposis and/or colorectal cancer, is instead performed, note that you would likely be testing this patient for several conditions that are not associated with childhood onset. • If the most likely condition is confirmed, what management recommendations would you make for this patient and his family? • See JPS management section within Chapter 6 for more information. • JPS can be due to inherited or de novo mutations. The patient’s parents should be offered targeted testing.
Case 3 A 6-week-old female presented with signs of impaired intestinal motility, including failure to pass meconium, constipation, and abdominal distention. Hirschsprung disease was confirmed with suction biopsies of the rectal
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mucosa and submucosa. A genetics consult was requested, and her physical examination was otherwise negative. Her parents were both present, and no dysmorphic features were noted. Her pedigree is below (Fig. 10.3). • What are the potential etiologies to consider for Hirschsprung disease?4 • Sporadic • Chromosomal causes (e.g., Down Syndrome) • Monogenic disorders • Nonsyndromic Hirschsprung disease • Syndromic Hirschsprung disease • What should the work-up include?4 • Detailed family history (Fig. 10.3) • Family history is remarkable for her father’s history of medullary thyroid cancer, which raises suspicion for multiple endocrine neoplasia type 2 (MEN2). • Physical examination • Negative, reduces likelihood of many syndromic causes of Hirschsprung disease. • For more information, see GeneReviews Hirschsprung Disease Overview.4 • Molecular genetic testing • Given her negative physical examination, family history of medullary thyroid cancer, and lack of signs of MEN2B in her parents
(see MEN2B section within Chapter 6 for more information), MEN2A or familial medullary thyroid cancer (FMTC) are most likely. RET testing should be performed. This can begin with sequencing of exons 10, 11, and 13–16 because most disease-causing mutations are located within these exons.5 If this testing is negative, full sequence analysis could be performed reflexively. Alternatively, full RET sequencing could be considered as a first-line test. • If the most likely condition is confirmed, what management recommendations would you make for the patient and her family? • See MEN2A/FMTC management section within Chapter 6 for more information. • The vast majority of cases of MEN2A/FMTC are due to a mutation that has been inherited from a parent.5 Targeted testing should be offered to her father first, given this personal history of MTC.
Case 4 An 8-year-old male presents with pervasive developmental disorder not otherwise specified (autism). His medical history is otherwise unremarkable. His pedigree is included below (Fig. 10.4).
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50
31
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Legend Autism - Autism Macrocephaly
8 6 Autism Macrocephaly Case 4 Pt FIG. 10.4 An 8-year-old male presents with pervasive developmental disorder not otherwise specified (autism). 10
CHAPTER 10 Case Examples
REFERENCES 1. M cKusick V, Tiller G. OMIM Entry – # 202300-Adrenocortical Carcinoma, Hereditary; ADCC. Omimorg; 2016. Available at: https://www.omim.org/entry/202300. 2. McKusick V, Hamosh A. OMIM Entry – # 114480-Breast Cancer. Omimorg; 2016. Available at: https://www.omim. org/entry/114480. 3. Haidle J, Howe J. Juvenile Polyposis Syndrome. Ncbinlmnihgov; 2016. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK1469/#jps. 4. Parisi M. Hirschsprung Disease Overview. Ncbinlmnihgov; 2016. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK1439/.
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5. M arquard J, Eng C. Multiple Endocrine Neoplasia Type 2. Ncbinlmnihgov; 2016. Available at: https://www.ncbi.nlm. nih.gov/books/NBK1257/#men2.
FURTHER READING 1. S chaefer G, Mendelsohn N. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399–407. http://dx.doi.org/10.1038/gim.2013.32.
Case Examples MEAGAN B. FARMER, MS, CGC • NATHANIEL H. ROBIN, MD
SCENARIOS Case 1
A 4-year-old female is being treated for adrenocortical carcinoma. Her pedigree is included below (Fig. 10.1). • What is the differential based on the information provided? • What, if any, testing would you begin with? • If the most likely condition is confirmed, what management recommendations would you make for this patient and her family?
Case 2 A 9-year-old boy presents with significant rectal bleeding and associated anemia. He is found to have six hamartomatous colorectal polyps on colonoscopy. His physical examination is negative. His pedigree is included below (Fig. 10.2). • What is the differential based on the information provided? • What, if any, further assessment and/or testing would you begin with? • If the most likely condition is confirmed, what management recommendations would you make for this patient and his family?
Case 3 A 6-week-old female presented with signs of impaired intestinal motility, including failure to pass meconium, constipation, and abdominal distention. Hirschsprung disease was confirmed with suction biopsies of the rectal mucosa and submucosa. A genetics consult was requested, and her physical examination was otherwise negative. Her parents were both present, and no dysmorphic features were noted. Her pedigree is below (Fig. 10.3). • What are the potential etiologies to consider for Hirschsprung disease?4 • What should the work-up include?4 • If the most likely condition is confirmed, what management recommendations would you make for the patient and her family?
Case 4 An 8-year-old male presents with pervasive developmental disorder not otherwise specified (autism).
His medical history is otherwise unremarkable. His pedigree is included below (Fig. 10.4). Chromosomal microarray and Fragile X testing were ordered by his pediatrician and were negative. Physical examination is only remarkable for macrocephaly (57 cm). • What should the genetics work-up of autism include? • Consider this case according to the proposed framework for evaluation. • If the most likely condition is confirmed, what management recommendations would you make for the patient and his family?
SOLUTIONS Case 1 A 4-year-old female is being treated for adrenocortical carcinoma. Her pedigree is included below (Fig. 10.1). • What is the differential based on the information provided? • Li-Fraumeni syndrome (adrenocortical carcinoma, breast cancer)1 • Beckwith-Wiedemann syndrome (adrenocortical carcinoma)1 • BRCA-related hereditary breast and ovarian cancer (breast cancer)2 • What, if any, testing would you begin with? • Both adrenocortical carcinoma and early-onset breast cancer are associated with Li-Fraumeni syndrome.1 Given this, TP53 sequencing and deletion/duplication analysis should be performed. • If the most likely condition is confirmed, what management recommendations would you make for this patient and her family? • See Li-Fraumeni management recommendations in Chapter 6. • Neither parent has a personal history of cancer, but a TP53 mutation could have been inherited from either parent or be de novo. Parents should be offered testing, beginning with her father given the paternal grandmother’s history of early-onset breast cancer. 115
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55
32 Br 29
33
31
53
51
Legend Ad - Adrenal cancer Br - Breast cancer
27
30
25
4 Ad 4 Case 1 Pt FIG. 10.1 A 4-year-old female being treated for adrenocortical carcinoma.
Legend 65
Polyp-Ham - Colon polyp
64
60
62 Lun 61
Lun - Lung cancer
43
41
39
40
2 9 7 Polyp-Ham 9 Case 2 Pt FIG. 10.2 A 9-year-old boy presents with significant rectal bleeding and associated anemia.
CHAPTER 10 Case Examples
Legend
57
22
34
32 ThyM 30
56
29
117
55
27
25
Hirschsprung Dz ThyM - Thyroid cancer
5
6w 2 Hirschsprung Dz Case 3 Pt FIG. 10.3 A 6-week-old female presented with signs of impaired intestinal motility, including failure to pass meconium, constipation, and abdominal distention.
Case 2 A 9-year-old boy presents with significant rectal bleeding and associated anemia. He is found to have six hamartomatous colorectal polyps on colonoscopy. His physical examination is negative. His pedigree is included below (Fig. 10.2). • What is the differential based on the information provided? • Juvenile polyposis syndrome (hamartomatous polyps with anemia)3 • Cowden syndrome/PTEN hamartoma syndrome (hamartomatous polyps)3 • Peutz-Jeghers syndrome (hamartomatous polyps)3 • What, if any, further assessment and/or testing would you begin with? • Review of colon polyp pathology to determine whether polyps appear to be juvenile type • If he has more than five juvenile-type polyps of the colorectum, he meets clinical diagnostic criteria for juvenile polyposis syndrome (see JPS section within Chapter 7 for more information). • Physical examination was reportedly negative. Confirm that head circumference is within normal limits and that there are no mucocutaneous findings suggestive of Peutz-Jeghers syndrome
to reduce suspicion for Cowden syndrome and Peutz-Jeghers syndrome, respectively. • If the above assessment confirms suspicion of juvenile polyposis syndrome, perform BMPR1A and SMAD4 sequencing and deletion/duplication analysis. If a multigene panel, including analysis of several genes implicated in susceptibility to polyposis and/or colorectal cancer, is instead performed, note that you would likely be testing this patient for several conditions that are not associated with childhood onset. • If the most likely condition is confirmed, what management recommendations would you make for this patient and his family? • See JPS management section within Chapter 6 for more information. • JPS can be due to inherited or de novo mutations. The patient’s parents should be offered targeted testing.
Case 3 A 6-week-old female presented with signs of impaired intestinal motility, including failure to pass meconium, constipation, and abdominal distention. Hirschsprung disease was confirmed with suction biopsies of the rectal
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mucosa and submucosa. A genetics consult was requested, and her physical examination was otherwise negative. Her parents were both present, and no dysmorphic features were noted. Her pedigree is below (Fig. 10.3). • What are the potential etiologies to consider for Hirschsprung disease?4 • Sporadic • Chromosomal causes (e.g., Down Syndrome) • Monogenic disorders • Nonsyndromic Hirschsprung disease • Syndromic Hirschsprung disease • What should the work-up include?4 • Detailed family history (Fig. 10.3) • Family history is remarkable for her father’s history of medullary thyroid cancer, which raises suspicion for multiple endocrine neoplasia type 2 (MEN2). • Physical examination • Negative, reduces likelihood of many syndromic causes of Hirschsprung disease. • For more information, see GeneReviews Hirschsprung Disease Overview.4 • Molecular genetic testing • Given her negative physical examination, family history of medullary thyroid cancer, and lack of signs of MEN2B in her parents
(see MEN2B section within Chapter 6 for more information), MEN2A or familial medullary thyroid cancer (FMTC) are most likely. RET testing should be performed. This can begin with sequencing of exons 10, 11, and 13–16 because most disease-causing mutations are located within these exons.5 If this testing is negative, full sequence analysis could be performed reflexively. Alternatively, full RET sequencing could be considered as a first-line test. • If the most likely condition is confirmed, what management recommendations would you make for the patient and her family? • See MEN2A/FMTC management section within Chapter 6 for more information. • The vast majority of cases of MEN2A/FMTC are due to a mutation that has been inherited from a parent.5 Targeted testing should be offered to her father first, given this personal history of MTC.
Case 4 An 8-year-old male presents with pervasive developmental disorder not otherwise specified (autism). His medical history is otherwise unremarkable. His pedigree is included below (Fig. 10.4).
52
50
31
50
30
48
28
Legend Autism - Autism Macrocephaly
8 6 Autism Macrocephaly Case 4 Pt FIG. 10.4 An 8-year-old male presents with pervasive developmental disorder not otherwise specified (autism). 10
CHAPTER 10 Case Examples
REFERENCES 1. M cKusick V, Tiller G. OMIM Entry – # 202300-Adrenocortical Carcinoma, Hereditary; ADCC. Omimorg; 2016. Available at: https://www.omim.org/entry/202300. 2. McKusick V, Hamosh A. OMIM Entry – # 114480-Breast Cancer. Omimorg; 2016. Available at: https://www.omim. org/entry/114480. 3. Haidle J, Howe J. Juvenile Polyposis Syndrome. Ncbinlmnihgov; 2016. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK1469/#jps. 4. Parisi M. Hirschsprung Disease Overview. Ncbinlmnihgov; 2016. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK1439/.
119
5. M arquard J, Eng C. Multiple Endocrine Neoplasia Type 2. Ncbinlmnihgov; 2016. Available at: https://www.ncbi.nlm. nih.gov/books/NBK1257/#men2.
FURTHER READING 1. S chaefer G, Mendelsohn N. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399–407. http://dx.doi.org/10.1038/gim.2013.32.