preauricular pits

Bosma Arhinia Microphthalmia Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia or clinical anophthalmia are usually present.  Iris colobomas are frequent features.  Occluded or absent nasolacrimal ducts have been reported.

Systemic Features: 

Arhina with anosmia is the most striking feature but it is usually accompanied by midface hypoplasia, a highly arched (or cleft) palate, and preauricular pits.  The nasal bones along with the cribriform plate, and other septal structures may be missing.  Maxillary and paranasal sinuses, together with the olfactory bulbs are often absent.  Intelligence is usually normal.

Choanal atresia is often present.  Hypogonadotropic hypogonadism with micropenis and cryptorchidism is an important feature in males.  Females may experience pubertal delay with menarche anomalies.  

Genetics

Heterozygous mutations in the SMCHD1 gene (18p11) are responsible for this disorder.  There is considerable clinical heterogeneity with many carriers having only minor manifestations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general disorder has been described.

References
Article Title: 

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Gordon CT, Xue S, Yigit G, Filali H, Chen K, Rosin N, Yoshiura KI, Oufadem M, Beck TJ, McGowan R, Magee AC, Altmuller J, Dion C, Thiele H, Gurzau AD, Nurnberg P, Meschede D, Muhlbauer W, Okamoto N, Varghese V, Irving R, Sigaudy S, Williams D, Ahmed SF, Bonnard C, Kong MK, Ratbi I, Fejjal N, Fikri M, Elalaoui SC, Reigstad H, Bole-Feysot C, Nitschke P, Ragge N, Levy N, Tuncbilek G, Teo AS, Cunningham ML, Sefiani A, Kayserili H, Murphy JM, Chatdokmaiprai C, Hillmer AM, Wattanasirichaigoon D, Lyonnet S, Magdinier F, Javed A, Blewitt ME, Amiel J, Wollnik B, Reversade B. De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nat Genet. 2017 Feb;49(2):249-255.

PubMed ID: 
28067911

Coloboma, Microphthalmia, Albinism, and Deafness

Clinical Characteristics
Ocular Features: 

A 5 year old male has been described with uveal colobomas in microphthalmic eyes plus small corneas with a pannus, dense cataracts, translucent irides, and hypopigmentation of the skin, hair and eyes.  A brain MRI showed hypoplasia of the optic nerves and chiasm.   

A 9 month old female from another family had severe microphthalmia and small optic nerves.  The internal ocular features were not reported.

Systemic Features: 

The complete phenotype is uncertain since it is based on only two reported and unrelated individuals.  The head circumference one one patient was consistent with macrocephaly accompanied by frontal bossing, shallow orbits, preauricular pits and posteriorly rotated ears.  A skeletal survey revealed evidence for osteopetrosis.  He had a sensorineural hearing deficit said to be congenital in onset.

The other patient, a 9 month old female, belonged to another nonconsanguineous family, and had similar skeletal and craniofacial features with the addition of micrognathia and hypotonia.  Congenital neurosensory hearing loss and general lack of pigmentation were noted.

All four parents have congenital sensorineural hearing loss, blue irides and fair skin with premature graying of hair.  Four sibs in the two families have phenotypes similar to that of the parents.  Only one child, a female, had no features of the phenotype.

Genetics

This condition, so far reported only in a male and a female in unrelated families, is the result of doubly heterozygous mutations in the MITF gene (3p13).  One mutation that causes Waardenburg syndrome 2  (WS2A) (193510) is combined with a dominant-negative allele (c.952_954delAGA [p.Arg318del]) to produce the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mandibulofacial Dysostosis with Alopecia

Clinical Characteristics
Ocular Features: 

The extensive dysplasia of the facial bones involves those of the orbital rims and zygomatic arches.  The orbital rims can be malformed and there is often a broad depression at the inferolateral region of the eyes.  Hypoplasia or even aplasia of the eyelids maybe present and some individuals have colobomas of the lower eyelids.  The lacrimal punctae may be temporally displaced.  The eyebrows and eyelashes are often sparse as part of the generalized alopecia.

Systemic Features: 

This is a disorder of craniofacial development resulting in extensive malformations of facial bones and skin.  Different rates of development among these structures leads to facial asymmetry in many patients. Maxillary, zygomatic arch, and mandibular bones are dysplastic resulting in micrognathia and a flat midface.   The temporomandibular joints are absent and the external ear canals are often incompletely formed.  Conductive hearing loss is common with hypoplastic ossicular chains while the pinnae are low-set, crumpled and abnormally cupped.  There may be preauricular tags or pits present.  Tooth eruption is often delayed and there may be agenesis of many permanent teeth.  The maxillary sinuses may be absent.  Cleft palate is often present.

Genetics

Heterozygous mutations in the EDNRA gene (4q31) are responsible for this condition.  No familial cases have been reported and it can be assumed that the mutations arise de novo. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual anomalies such as the colobomas, dental deformities and cleft palate may be surgically repaired.  Upper airway obstruction may require tracheostomy in infants.

References
Article Title: 

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia

Gordon CT, Weaver KN, Zechi-Ceide RM, Madsen EC, Tavares AL, Oufadem M, Kurihara Y, Adameyko I, Picard A, Breton S, Pierrot S, Biosse-Duplan M, Voisin N, Masson C, Bole-Feysot C, Nitschke P, Delrue MA, Lacombe D, Guion-Almeida ML, Moura PP, Garib DG, Munnich A, Ernfors P, Hufnagel RB, Hopkin RJ, Kurihara H, Saal HM, Weaver DD, Katsanis N, Lyonnet S, Golzio C, Clouthier DE, Amiel J. Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia. Am J Hum Genet. 2015 Apr 2;96(4):519-31.

PubMed ID: 
25772936

Microphthalmia, Syndromic 7

Clinical Characteristics
Ocular Features: 

Microphthalmia and rarely clinical anophthalmia are the ocular hallmarks of this disorder.  Corneal leukomas and some degree of sclerocornea are usually present as well.  Orbital cysts have been observed.  Other less consistent findings include iridocorneal adhesions, glaucoma, microcornea, cataracts, aniridia, persistence of the anterior hyaloid artery and other vitreous opacities, and patchy hypopigmentation of the RPE.

Systemic Features: 

The skin on the nose, cheeks and neck has linear red rashes and scar-like lesions.  Biopsy of these has revealed smooth muscle hemartomata rather than simple dermal aplasia.  There may be some healing of the skin defects.  The corpus callosum is sometimes absent.  Diaphragmatic hernias are often present.  Cardiac abnormalities include hypertrophic cardiomyopathy, arrhythmias, and septal defects.   Preauricular pits and hearing loss have been found in some patients.  Patients may be short in stature and some have nail dysplasia.  GU and GI anomalies may be present.

Genetics

This is an X-linked dominant disorder with lethality in the hemizygous male.  Many patients (79%) have interstitial deletions of the Xp22.2 region of the X chromosome.  Sequence analysis of this region has revealed heterozygous point mutations in the HCCS gene (Xp22.2) in numerous other patients.  In several additional cases deleterious mutations have been found in the X-linked COX7B gene.  However, familial occurrence is uncommon.  X chromosome inactivation may be skewed with the abnormal X being inactive in virtually all cases. Several 46 XX males with this syndrome have been described.

Goltz syndrome (305600), also called focal dermal hypoplasia, may have similar skin and ocular findings but the limb anomalies are not found in the disorder described here.  Goltz syndrome (305600) is the result of mutations in PORCN at another locus on the X chromosome and is thus unrelated.

Other X-linked dominant disorders with lethality in hemizygous males and abnormalities in skin and the eye are Incontinentia pigmenti (308300) and Aicardi syndrome (304050).  The skin lesions and ocular anomalies are dissimilar to those in MLS and they often have far more severe CNS abnormalities.   Further, the mutation causing Aicardi is in the NEMO (IKBKG) gene at another location on the X chromosome.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Treatment is organ-specific with repair of septal defects and diaphragmatic hernias.  Progressive orbital prosthetics should be considered in patients with blind, microphthalmic and clinically anophthalmic eyes.

References
Article Title: 

Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern

Ogata T, Wakui K, Muroya K, Ohashi H, Matsuo N, Brown DM, Ishii T, Fukushima Y. Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern. Hum Genet. 1998 Jul;103(1):51-6. Review.

PubMed ID: 
9737776

Carpenter Syndrome

Clinical Characteristics
Ocular Features: 

A variety of ocular anomalies have been reported in Carpenter syndrome with none being constant or characteristic.  The inner canthi are often spaced widely apart and many have epicanthal folds and a flat nasal bridge.  Other reported abnormalities are nystagmus, foveal hypoplasia, corneal malformations including microcornea, corneal opacity, and mild optic atrophy and features of pseudopapilledema.

Systemic Features: 

Premature synostosis involves numerous cranial sutures with the sagittal suture commonly involved causing acrocephaly (tower skull).  Asymmetry of the skull and a 'cloverleaf' deformity are often present.  The polydactyly is preaxial and some degree of syndactyly is common especially in the toes.  The digits are often short and may be missing phalanges.  Some patients are short in stature.  Structural brain defects may be widespread including atrophy of the cortex and cerebellar vermis.  Septal defects in the heart are found in about one-third of patients.  The ears can be low-set and preauricular pits may be seen.  Some but not all patients have obesity and a degree of mental retardation.

Genetics

This is an autosomal recessive syndrome caused by a mutation in the RAB23 gene (6p12.1-q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment of the ocular defects is necessary in most cases. Craniectomy may be required in cases with severe synostosis.

References
Article Title: 

Carpenter syndrome

Hidestrand P, Vasconez H, Cottrill C. Carpenter syndrome. J Craniofac Surg. 2009 Jan;20(1):254-6.

PubMed ID: 
19165041

RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity

Jenkins D, Seelow D, Jehee FS, Perlyn CA, Alonso LG, Bueno DF, Donnai D, Josifova D, Mathijssen IM, Morton JE, Orstavik KH, Sweeney E, Wall SA, Marsh JL, Nurnberg P, Passos-Bueno MR, Wilkie AO. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet. 2007 Jun;80(6):1162-70. Erratum in: Am J Hum Genet. 2007 Nov;81(5):1114. Josifiova, Dragana [corrected to Josifova, Dragana].

PubMed ID: 
17503333

Peters-Plus Syndrome

Clinical Characteristics
Ocular Features: 

Peters anomaly (306229) usually occurs as an isolated ocular malformation and is often unilateral.  However, in some patients with bilateral involvement it is part of a systemic syndrome or other congenital conditions such as chromosomal deletions and the fetal alcohol syndrome.  It is called Peters Plus syndrome in the condition described here because of the association of a specific combination of systemic features.

The ocular features are consistent with dysgenesis of the anterior chamber.  The clinical picture is highly variable but generally consists of iris adhesions to the cornea centrally (classical Peters anomaly), occasionally lenticular adhesions as well, and thinning of the central corneal stroma.  As a result, the cornea may become edematous, cataracts may develop, and glaucoma is common.

Systemic Features: 

Peters-plus syndrome consists of Peters anomaly plus various degrees of developmental delays and intellectual deficits, short digits and short stature, and cleft lip and palate.  The facies is said to be characteristic due to a prominent forehead, narrow palpebral fissures, and a cupid's bow-shaped upperlip. There may be preauricular pits present and the neck is often broad.  The ears may be prominent.  Congenital heart defects are present in a third of patients and a few have genitourinary anomalies.

Genetics

This is an autosomal recessive disorder of glycosylation caused by a mutation in the B3GALTL gene on chromosome 13 (13q12.3).  At least some patients have a splicing mutation in this gene leading to a skipping of exon 8.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at sight preservation by correcting the major ocular defects such as glaucoma and iridocorneal adhesions.  Corneal transplants and cataract removal are sometimes required.  Releasing the anterior synechiae can lead to significant clearing of the corneal edema.  Growth hormone replacement therapy may be beneficial.

References
Article Title: 

The Peters' plus syndrome: a review

Maillette de Buy Wenniger-Prick LJ, Hennekam RC. The Peters' plus syndrome: a review. Ann Genet. 2002 Apr-Jun;45(2):97-103. Review.

PubMed ID: 
12119218
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