MIM

154700

Clinical features

Skeletal problems, including arachnodactyly, pectus deformities of the chest, joint laxity, and scoliosis (see Figure 17). Cardiac abnormalities include mitral or aortic regurgitation, a dilated aortic root, and aortic aneurysms. Ocular abnormalities are common, and include myopia and, occasionally, lens dislocation. Connective tissue weakness can cause hernia, lumbar striae, pneumothorax, and a narrow, high-arched palate.

Figure 17

Marfanoid habitus.

Gene

FBN1 (fibrillin 1)

Chromosomal location

15q21

Prevalence

1 in 14,000 births

Inheritance

Autosomal dominant

History

Described by Bernard Marfan, the foundation Professor of Pediatrics in Paris, in 1896.

Age at onset

Congenital forms occur, but are rare and have severe cardiac involvement. Most forms are obvious; patients present with tall stature in childhood and heart defects.

Diagnosis

Clinical examination and defined criteria requiring the major involvement of two organ systems and minor involvement of a third system.

Genetic testing

Genetic testing is available for FBN1 mutations and several have been described, with no major common mutation.

Screening

Should include annual ophthalmic examination and regular echocardiographic screening to detect aortic root dilatation. Strenuous or very competitive sports (eg, weightlifting) should be avoided due to potential heart and joint problems.

Mutational spectrum

Heterogeneity exists with FBN2 mutations found in Beal's syndrome (congenital contractural arachnodactyly) and is similar to Marfan's syndrome, but without the cardiac features. Other causes of a Marfanoid habitus include familial ectopia lentis (MIM 129600), Ehlers–Danlos syndrome, familial mitral valve prolapse, and multiple endocrine neoplasia type IIB.

Counseling issues

As for other disorders with autosomal dominant inheritance. Careful examination and fulfilling of the criteria are important to exclude other conditions listed above. Penetrance is variable, and not all families have the eye changes or the tall stature.

MIM

163950

Clinical features

Short stature and a short, webbed neck. Cardiac anomalies (particularly pulmonary stenosis, atrial septal defect, ventriculoseptal defect, patent ductus arteriosus, and hypertrophic cardiomyopathy), and chest deformity (pectus carinatum superiorly and pectus excavatum inferiorly), wide-spaced nipples, and a characteristic dysmorphic facial appearance with ptosis of the eyelids and wiry hair (see Figure 18).

Figure 18

Wiry hair and a low hairline, characteristic of Noonan's syndrome.

Gene

PTPN11 (protein-tyrosine phosphatase nonreceptor-type, 11)

Chromosomal location

12q24

Inheritance

Autosomal dominant

Age at onset

Neonatal onset with cardiac problems and feeding difficulties.

Diagnosis

Clinical with confirmation on genetic testing in difficult cases.

Genetic testing

Available in research centers.

Screening

Cardiac problems are the most severe. Screen with echocardiography.

Counseling issues

Autosomal dominant inheritance with variable penetrance, so the affected parent should be screened for latent cardiac problems. Around 10% of affected individuals have learning and schooling problems, and coagulation abnormalities can be a problem.

MIM

190685

Clinical features

Various malformations, including simian creases (see Figure 19). Several surgical problems, including congenital heart disease, increased incidence of goiter, umbilical and groin hernias, and macroglossia.

Figure 19

A simian crease.

Gene

Complete trisomy of chromosome 21

Chromosomal location

Chromosome 21

Prevalence

1 in 600 live births

Inheritance

Chromosomal: 95% of cases are the result of age-related nondysjunction, 3% result from familial translocation (where two or more chromosomes have segments shared or exchanged), and 2% are mosaic cases. In mosaic cases, some cell lines have normal chromosomes and others have the extra cell line – this may allow a milder phenotype, particularly if brain tissue has the normal chromosome complement and blood has the extra cell line.

History

Described by Langdon Down, an English physician, in 1887.

Age at onset

Congenital, although rare milder mosaic cases may not be recognized until adolescence.

Diagnosis

Chromosome analysis will confirm a diagnosis suspected on clinical grounds.

Screening

Prenatal diagnosis by maternal serum screening (in the first or second trimester), ultrasound (neck-fold thickness, nasal bone appearance, and structural markers in the first and second trimester), and amniocentesis (from 15 weeks onwards).

Counseling issues

Recurrence risks by age are available for parents wishing to have a further child after one child with Down's syndrome. Typical risks are around 1 in 100, but around 1 in 10 if the affected child has translocation Down's syndrome.

MIM

160980 (Carney complex type I [CNC1]; also known as NAME or LAMB syndromes)

605244 (Carney complex type II [CNC2])

Clinical features

Spotty pigmentation, cardiac and other myxomas, endocrine tumor –also known by the acronyms NAME (Nevi, Atrial myxoma, Myxoid neurofibromata, Ephelides) and LAMB (Lentigines, Atrial myxoma, Myxoid tumors, Blue nevi)

Gene

PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, α; CNC1). Unknown for CNC2.

Chromosomal location

17q23–q24 (CNC1), 2p16 (CNC2)

Prevalence

Extremely rare

Inheritance

Autosomal dominant

Age at onset

Atrial myxomas develop during childhood.

Diagnosis

A distinctive combination of dermatological and cardiac clinical features is suggestive of the diagnosis. Confirmed by cardiac echocardiography and gene testing.

Genetic testing

Available for PRKAR1A on a research basis. Around 50% of patients have CNC1. In patients who do not have CNC1, linkage analysis may allow testing for the CNC2 locus on 2p16 in large families, but this is only available on a research basis.

Screening

Gene carriers for cutaneous tumors and cardiac echocardiography in childhood. Endocrine problems, including Cushing's syndrome and Sertoli cell tumors of the testis, have been reported.

Mutational spectrum

Heterogeneity exists. At least two CNC types and gene loci are known and further types may exist.

Mitral Valve

Individuals with familial mitral valve prolapse (MIM 157700) have displacement or billowing of the mitral valve leaflets into the left atrium. Complications include fatal arrhythmias, endocarditis, and even sudden death. Inheritance is autosomal dominant, with one locus on 16p11.2 (myxomatous mitral valve prolapse 1 [MMPV1]), a second on 11p15.4 (MMPV2), and an X-linked type on Xq28. Heterogeneity exists, with several families described. Associations with connective tissue disorders, Ehlers–Danlos syndrome, cutis laxa, pseudoxanthoma elasticum, osteogenesis imperfecta, and Marfan's syndrome should be excluded.

Aortic Valve

Aortic stenosis associated with Williams' syndrome, a chromosomal microdeletion defect of the ELN (elastin) gene on chromosome 7. Some patients with Noonan's syndrome may also have aortic valve defects.

Pulmonary Valve

Rarely has a familial cause. Noonan's syndrome is associated with pulmonary stenosis.

Tricuspid Valve

Tricuspid atresia is common in 1%–3% of cardiac defects. Familial autosomal dominant disease is rare, but has been reported (MIM 605067).

Atrial Septum

Isolated atrial septal defect (ASD) is often familial – one locus on 6p21.3 ( ASD1 , MIM 108800) is autosomal dominant. It is also associated with numerous congenital malformation syndromes, including Holt–Oram syndrome (autosomal dominant inheritance and cardiac or limb defects), due to mutations in the NKX2-5 gene

Ventricular Septum

Hereditary isolated ventricular septal defects are rare, but when they do occur they are often associated with congenital malformation syndromes (including Down's syndrome and arteriovenous canal defects). The GATA4 (GATA-binding protein 4) gene on 8p22–p23 is associated with autosomal dominant septal defects, including atrial septal defect and pulmonary valve thickening.

Patent Ductus Arteriosus

This is the second most common cardiac defect, occurring in 1 in 3,000 live births. After prematurity, genetic causes are common, but most are found in congenital malformation syndromes. Familial forms exist and can be either autosomal dominant (MIM 607411) or autosomal recessive. The recurrence risk in siblings is around 5%.