midface hypoplasia

SHORT Syndrome

Clinical Characteristics
Ocular Features: 

Deeply set eyes are frequently noted and perhaps are a result of the lipodystrophy.  Anterior segment abnormalities resembling Rieger anomalies are often associated with congenital glaucoma. 

Systemic Features: 

There is considerable clinical heterogeneity.  The facial gestalt, however, is said to be characteristic.  These are: triangular progeroid facies with a prominent forehead, absence of facial fat, midface hypoplasia, and hypoplastic nasal alae.  Insulin resistance seems to be a consistent feature as well and nephrocalcinosis is common.  Serum and urinary calcium may be elevated even in infancy.

Teeth are late to erupt and bone age is delayed with shortness of stature the final result in many cases.  Joints are often hyperextensible.  A neurosensory hear loss has been found in some individuals.  Notably, developmental milestones are usually timely although mild cognitive delays are rarely seen and speech may be delayed.  Inguinal hernias are part of the syndrome. 

Genetics

Heterozygous mutations in the PIK3R1 gene (5q31.1) are responsible for this syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Serum and urinary calcium should be monitored.  The risk of glaucoma is high and patients should be monitored and treated appropriately.  Blood sugar and insulin levels may require treatment.  Inguinal hernias may require surgical repair.

References
Article Title: 

Mutations in PIK3R1 cause SHORT syndrome

Dyment DA, Smith AC, Alcantara D, Schwartzentruber JA, Basel-Vanagaite L, Curry CJ, Temple IK, Reardon W, Mansour S, Haq MR, Gilbert R, Lehmann OJ, Vanstone MR, Beaulieu CL; FORGE Canada Consortium., Majewski J, Bulman DE, O'Driscoll M, Boycott KM, Innes AM. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013 Jul 11;93(1):158-66. 

PubMed ID: 
23810382

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

ZTTK Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are deep-set and the palpebral fissures slant downward.  Optic atrophy is often present.  The majority of individuals have poor visual responses which may also be attributed to central or cortical impairment.  Strabismus and nystagmus are frequently present.

Systemic Features: 

ZTTK syndrome is multisystem malformation and developmental disorder with a heterogeneous clinical presentation.  The facial features might suggest the diagnosis at birth but most of the signs are nonspecific including frontal bossing, underdevelopment of the midface, facial asymmetry, low-set ears, broad and/or depressed nasal bridge, and a short philtrum.  Poor feeding and hypotonia in the neonatal period are usually present and physical growth is subnormal resulting in short stature.

Brain imaging may show abnormal gyral patterns, ventriculomegaly, hypoplasia of the corpus callosum, cerebellar hypoplasia, arachnoid cysts, and loss of periventricular white matter.  About half of patients develop seizures and many have intellectual disabilities.  Spinal anomalies include hemivertebrae with scoliosis and/or kyphosis.  Other skeletal features include joint laxity in some patients and contractures in others.  Arachnodactyly, craniosynostosis, and rib anomalies have been reported.  There may be malformations in the GI, GU, and cardiac systems while immune and coagulation abnormalities have also been reported.

Genetics

Heterozygous mutations in the SON gene (21q22.11) have been identified in patients with this condition.  They may cause truncation of the gene product with haploinsufficiency or, in other patients, a frameshift in the reading.  The SON gene is a master RNA splicing regulator that impacts neurodevelopment.

Virtually all cases are the result of de novo mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.  Physical therapy and assistive devices may be helpful.

References
Article Title: 

De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive

Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Kury S, Besnard T, Isidor B, Latypova X, Bezieau S, Liu P, Motter CS, Melver CW, Robin NH, Infante EM, McGuire M, El-Gharbawy A, Littlejohn RO, McLean SD, Bi W, Bacino CA, Lalani SR, Scott DA, Eng CM, Yang Y, Schaaf CP, Walkiewicz MA. De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive. Am J Hum Genet. 2016 Sep 1;99(3):720-7.

PubMed ID: 
27545676

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Kim JH, Shinde DN, Reijnders MR, Hauser NS, Belmonte RL, Wilson GR, Bosch DG, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel CT, Draaisma JM, Nicolai J; University of Washington Center for Mendelian Genomics, Yntema HG, Lindstrom K, de Vries BB, Jewett T, Santoro SL, Vogt J; Deciphering Developmental Disorders Study, Bachman KK, Seeley AH, Krokosky A, Turner C, Rohena L, Hempel M, Kortum F, Lessel D, Neu A, Strom TM, Wieczorek D, Bramswig N, Laccone FA, Behunova J, Rehder H, Gordon CT, Rio M, Romana S, Tang S, El-Khechen D, Cho MT, McWalter K, Douglas G, Baskin B, Begtrup A, Funari T, Schoch K, Stegmann AP, Stevens SJ, Zhang DE, Traver D, Yao X, MacArthur DG, Brunner HG, Mancini GM, Myers RM, Owen LB, Lim ST, Stachura DL, Vissers LE, Ahn EY. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet. 2016 Sep 1;99(3):711-9.

PubMed ID: 
27545680

Takenouchi-Kosaki Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype consists of mild ptosis, synophrys, exotropia, and eversion of the lower eyelids.  One of two reported patients was described as having bilateral retinal dysplasia and a falciform retinal detachment in one eye.  Visual acuity is significantly impaired.

Systemic Features: 

Affected individuals may be of normal birth weight but skeletal growth is subnormal and there is general developmental delay.  Congenial cardiac anomalies such as persistent ductus arteriosus may be present.  Lymphedema has been noted at one year of age and probably persists throughout life.  Protein-losing enteropathy secondary to intestinal lymphangiectasia was present in one individual.  The same patient had pericardial effusion, hydrothorax, and ascites.  Intellectual disability may be severe although there is no evidence of progression.  Neurosensory hearing loss has been described in one patient.

Thrombocytopenia is a consistent finding and has been described as early as one year of age.  Platelet numbers as low as 52,000/microL have been recorded and appear larger than normal. 

Genetics

Both unrelated female patients reported have heterozygous missense mutations in the CDC42 gene (1p36). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Acrofacial Dysostosis, Cincinnati Type

Clinical Characteristics
Ocular Features: 

The periocular features are part of the general facial dysmorphism.  The lid fissures slant downward, and the orbits appear inferiorly displaced.  'Clefts' (colobomas?) of the lower eyelids and sometimes the upper may be evident.  The medial eyelashes were absent in one patient. 

Systemic Features: 

The extraocular features reported so far are based on only three patients and there is considerable variation.  The head is usually small and patients may be short in stature.  The zygomatic arches, the maxillae and the mandibles are hypoplastic as is the midface.  There may be anotia and severe conductive hearing loss.  The pinnae can be large and are sometimes low-set.  Inconsistent short limbs with hip dysplasia and femoral bowing have been reported.  Brachydactyly is also a feature.

Genetics

Heterozygous mutations in the POLR1A gene (2p11) seem to be responsible for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the overall condition but individual anomalies such as lid 'clefts' can be surgically repaired. Severe micrognathia may require tracheostomy at birth.

References
Article Title: 

Cole-Carpenter Syndrome 2

Clinical Characteristics
Ocular Features: 

Postnatally the eyes are prominent and hypertelorism has been reported.  The palpebral fissures slant downward and the root of the nose is angular. 

Systemic Features: 

This is primarily a skeletal disorder with impaired skull ossification and multiple bone fractures of prenatal origin.  It is sometimes confused with forms of osteogenesis imperfecta.  The skull is poorly ossified and frequent diaphyseal fractures of the long bones occur leading to motor delays and short stature.  Rib fractures are sometimes seen. Intelligence seems to be normal.  A receding chin has been noted and the hard palate is highly vaulted.  The midface is flat.

Genetics

This disorder results from compound heterozygous mutations in the SEC24D gene (4q26).  Only a few patients have been reported.

For a somewhat similar but autosomal dominant disorder see Cole-Carpenter Syndrome 1 (112240).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Physical activity should be restricted to noncontact sports and where the cranium has ossification defects a helmet should be worn.  Fractures should be appropriately treated.

References
Article Title: 

Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta

Garbes L, Kim K, Riess A, Hoyer-Kuhn H, Beleggia F, Bevot A, Kim MJ, Huh YH, Kweon HS, Savarirayan R, Amor D, Kakadia PM, Lindig T, Kagan KO, Becker J, Boyadjiev SA, Wollnik B, Semler O, Bohlander SK, Kim J, Netzer C. Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta. Am J Hum Genet. 2015 Mar 5;96(3):432-9.

PubMed ID: 
25683121

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

GAPO Syndrome

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is considered part of this syndrome but it is not a consistent feature.  One patient with the suspected diagnosis had papilledema while other individuals may have congenital glaucoma, buphthalmos, band keratopathy, and keratoconus.  White eyelashes have been described.  Myelinated nerve retinal nerve fibers may be prominent.

Systemic Features: 

This is a rare congenital disorder with so far incomplete phenotypic delineation. The diagnosis can be made soon after birth from the general facial and body morphology.  The dysmorphism is secondary to marked bone growth retardation and metaphyseal dysplasia, resulting in a flat midface, frontal bossing, micrognathism, chest deformities, and vertebral anomalies. Psychomotor retardation is common but the extent of cognitive deficits is unknown.  The permanent teeth may begin to develop but fail to erupt (pseudoanodontia). Even primary dentition is often abnormal.  Alopecia is a feature although some individuals do have sparse body hair, at least for a period of time.  Anomalous blood vessels such as dilated scalp veins are sometimes evident.   Hypogonadism has been reported in both sexes.  Individuals are subject to recurrent ear and respiratory infections. 

Genetics

GAPO occurs in both sexes.  The presence of parental consanguinity in many families suggests autosomal recessive inheritance but no mutation or gene has been described.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at individual problems.  Prompt treatment of respiratory infections is important.

References
Article Title: 

Ophthalmic findings in GAPO syndrome

Ilker SS, Ozturk F, Kurt E, Temel M, Gul D, Sayli BS. Ophthalmic findings in GAPO syndrome. Jpn J Ophthalmol. 1999 Jan-Feb;43(1):48-52.

PubMed ID: 
10197743

Gurrieri Syndrome

Clinical Characteristics
Ocular Features: 

Tapetoretinal degeneration has been described in several patients.  Some patients have keratoconus with lens and corneal opacities.  Visual acuities have not been reported.  The full ocular phenotype must be considered unknown since most patients have not had full ophthalmic evaluations.

Systemic Features: 

Features of an osteodysplasia are among the most striking in this syndrome.  Short stature, brachydactyly, delayed bone age, osteoporosis, and hypoplasia of the acetabulae and iliac alae are usually present.  Birth weight is often low.  Joints may be hyperflexible as part of the generalized hypotonia. The eyes are deep-set, the nasal bridge is prominent, the midface is flat, and the supraorbital ridges are prominent giving the face a rather coarse look.  Prognathism with a prominent lower lip and dental malocclusion reinforce this appearance.  Seizures beginning in early childhood may be difficult to control.  Most patients have severe psychomotor retardation and never acquire speech.

Genetics

The genetics of this familial disorder remain unknown.  No locus or mutation has been identified but one patient had an absent maternal allele of the proximal 15q region as found in Angelman syndrome.

Orofaciodigital syndrome IX (258865) is another autosomal recessive syndrome sometimes called Gurrieri syndrome.  In Gurrieri’s original description of two brothers, chorioretinal lacunae, similar to those seen in Aicardi syndrome (304050), were present.  The systemic features are dissimilar, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Treacher Collins-Franceschetti Syndrome

Clinical Characteristics
Ocular Features: 

Lid fissures often have an antimongoloid slant.  Many patients (69%) have a coloboma of the lower eyelid (in contradistinction to Goldenhar spectrum syndrome [164210] in which the lid colobomas involve the upper eyelid) with a paucity of lashes and meibomian glands medially.  Colobomas may also involve the iris, choroid and optic nerve.  Other ocular features include blepharoptosis, hypoplasia of the supraorbital ridges, absent lacrimal puncti, underdevelopment of the orbicularis oculi muscle, absence of the tarsal plate, and abnormalities of the lateral canthal tendons.  Strabismus and amblyopia have been reported in a significant number of individuals.

Systemic Features: 

A variety of defects in facial development have been reported, most involving the ears, eyelids, lower jaw, and zygomatic arch.  The characteristic facial phenotype is usually evident at birth.  One-third of patients have a cleft palate.  Microtia or even anotia may be present and a conductive hearing loss can result, especially when the ossicles are malformed or absent.  The pinnae are often malformed, appearing 'crumpled', low-set, and rotated posteriorly.  There may be ear tags and blind fistulas anywhere between the tragus and angle of the mouth.  The mandible and its rami may be hypoplastic causing severe micrognathia that can result in feeding and speaking difficulties, especially when pharyngeal hypoplasia is also present.  The zygomatic arches are often underdeveloped (or even absent) and the midface is flattened.  Arhinia and cleft palate are sometimes seen.  A low hairline may be present.  Intelligence is usually normal.

Genetics

This is an autosomal dominant syndrome secondary to mutations in the TCOF1 gene located at 5q32-q33.1.  A parental gender influence is suggested by at least one study which found an increase in the number of affected offspring from affected mothers compared with those from affected fathers.  Many cases (60%) result from new mutations but a paternal age effect has not been established.  Inter- and intrafamilial clinical variation is wide.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Auditory testing should be done early since corrective action is important in the prevention of developmental delays.  Reconstructive facial surgery can be of great benefit to both cosmesis and function.  Lid reconstruction may be required for corneal protection.

References
Article Title: 

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

Teber OA, Gillessen-Kaesbach G, Fischer S, Bohringer S, Albrecht B, Albert A, Arslan-Kirchner M, Haan E, Hagedorn-Greiwe M, Hammans C, Henn W, Hinkel GK, Konig R, Kunstmann E, Kunze J, Neumann LM, Prott EC, Rauch A, Rott HD, Seidel H, Spranger S, Sprengel M, Zoll B, Lohmann DR, Wieczorek D. Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. Eur J Hum Genet. 2004 Nov;12(11):879-90.

PubMed ID: 
15340364

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