pyloric stenosis

Arthrogryposis, Perthes Disease, and Upward Gaze Palsy

Clinical Characteristics
Ocular Features: 

Upward gaze is restricted and attempts to do so are associated with exotropia.

Systemic Features: 

Arthrogryposis with restricted joint mobility is present in both proximal and distal joints, including hips, elbows, hands, and knees.  It is usually evident early in infancy when parents note "tight joints".  Other joint deformities present to some degree are "trigger finger" deformities found in the middle fingers and thumbs.  Hip pain and difficulty walking as early as 3 years of age can be signs of avascular necrosis of the femoral head (Perthes disease).   

Pyloric stenosis can lead to severe, recurrent vomiting.  Pulmonic stenosis is commonly present and there are often cardiac septal defects as well as valvular malfunctions.  Bronchial asthma is a feature.

Genetics

One extended consanguineous Saudi family with three affected females has been reported.  No similar findings are present in the parents and the condition is most likely transmitted as an autosomal recessive.  A homozygous mutation in NEK9 (14q24) has been associated with this condition.

Heterozygous mutations in the same gene have been identified in 3 patients with nevus comedonicus (617025).  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Flexion deformities may be at least partially alleviated by surgery and is especially beneficial for digital function.  Pyloric stenosis and cardiac valve disease may respond to surgery.

References
Article Title: 

Mutations in NEK9 Cause Nevus Comedonicus

Levinsohn JL, Sugarman JL; Yale Center for Mendelian Genomics, McNiff JM, Antaya RJ, Choate KA. Somatic Mutations in NEK9 Cause Nevus Comedonicus. Am J Hum Genet. 2016 May 5;98(5):1030-7.

PubMed ID: 
27153399

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

Shaheen R, Patel N, Shamseldin H, Alzahrani F, Al-Yamany R, ALMoisheer A, Ewida N, Anazi S, Alnemer M, Elsheikh M, Alfaleh K, Alshammari M, Alhashem A, Alangari AA, Salih MA, Kircher M, Daza RM, Ibrahim N, Wakil SM, Alaqeel A, Altowaijri I, Shendure J, Al-Habib A, Faqieh E, Alkuraya FS. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet Med. 2016 Jul;18(7):686-95.

PubMed ID: 
26633546

Beare-Stevenson Syndrome

Clinical Characteristics
Ocular Features: 

The midface hypoplasia and shallow orbits result in the appearance of prominent eyes.  Ptosis and hypertelorism have been reported while the palpebral fissures are downslanting. One patient has been reported to have optic atrophy.  Another patient was described with cloudy corneas, irregular irides and nonreactive pupils.

Systemic Features: 

Pregnancies may be complicated by polyhydramnios.  Infants are born with craniosynostosis with a cloverleaf pattern usually.  The skull is often shortened in the anteroposterior axis with flattening of the occipital region.  The skin is deeply furrowed with the cutis gyrata patterns most prominent in the posterior scalp but also present on the palms, soles, pinnae, and elsewhere.  Acanthosis nigricans is often present.

There is midface hypoplasia and nearly all individuals have intellectual disability.

The external ear canals can be atretic, the nares are often anteverted, and the mouth may be small.  An excess number of neonatal teeth and hypoplastic nails have been noted.  Hydrocephalus is common.  The umbilical stump is often unusually prominent.  Anogenital anomalies such as an anteriorly placed anus, cryptorchidism, and bifid scrotum may be present.  Pyloric stenosis is sometimes present.

Upper airway obstruction with respiratory distress may necessitate a tracheotomy. A cartilaginous tracheal sleeve replacing the normal C rings of cartilage has been found in several infants. These can be difficult to detect and their presence may have been responsible for breathing restrictions that has led to the demise of some children before two years of age.

Genetics

Reported cases have occurred sporadically.  Increased paternal age has been suggested as a factor in the occurrence of heterozygous mutations in the FGFR2 gene (10q26.13) which have been identified in some individuals.

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Crouzon Syndrome (123500), Pfeiffer Syndrome (101600), Apert Syndrome (101200), Jackson-Weiss Syndrome (123150), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no general treatment for this syndrome.  Several infants have had tracheotomies and CNS shunts.

References
Article Title: 

Beare-Stevenson cutis gyrata syndrome

Hall BD, Cadle RG, Golabi M, Morris CA, Cohen MM Jr. Beare-Stevenson cutis gyrata syndrome. Am J Med Genet. 1992 Sep 1;44(1):82-9. PubMed PMID: 1519658.

PubMed ID: 
1519658
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