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Gorlin-Chaudhry-Moss Syndrome

Gorlin-Chaudhry-Moss syndrome is an extremely rare genetic disease, part of the ectodermal dysplasia group, characterized by multiple bone abnormalities, conductive deafness, visual impairment and hypertrichosis.


Presentation

Gorlin-Chaudhry-Moss syndrome patients have numerous anomalies regarding appearance and several organs and systems. Premature skull sutures calcification leads to coronal craniosynostosis, but brachycephaly and turricephaly can also be encountered. Further dysmorphism is due to other bone abnormalities, such as depressed supraorbital ridges, prominent columella and midface hypoplasia. The facies also has several specific traits, like short and downslanted or upslanted palpebral fissures, hypertelorism, bifid nasal tip, underdeveloped ala nasi, small and posteriorly angulated ears. Hair abnormalities include generalized hypertrichosis even during the infancy, coarse hair, low anterior and posterior hairline and synophrys [1]. The facial features can coarsen over time [2].

Patients complain about hearing loss that proves to be of conductive type upon examination. An ophthalmologic consult may reveal an ectropion of the lower eyelid, corneal scars, nystagmus, astigmatism, sclerocornea, ocular coloboma, microphthalmia or hyperopia [3]. Lacrimal duct stenosis can be encountered.

Dental annomalies, such as an abnormal shape, oligodontia, malocclusion, microdontia or irregularly shaped teeth with wide spaces between them may coexist. The palate may be narrow, may present a medial cleft or may be high arched. Maxillary hypoplasia can be a cause for the dental particularities [4].

Close attention must be paid to the examination of the extremities. The distal phalanges are usually hypoplastic, as are the nails, with anonychia being another possibility. Metacarpal bones anomalies can be encountered. Cutaneous syndactyly may sometimes be noticed. Flexion creases of the thumbs are absent and the palmar creases are singular [5].

Other changes, unrelated to the bone system, include hypoplasia of labia majora or genital hypoplasia, umbilical hernia, congenital laryngomalacia and patent ductus arteriosus [6].

Short stature and growth retardation can be caused by the genetic mutation per se, by feeding impairment secondary to oral abnormalities or by heart failure secondary to the permeable arterial duct. When intrauterine growth retardation is observed, the cause most likely is attributable to the genotype [7]. In cases where congestive heart failure sets in, clinical examination can reveal dyspnea, cardiomegaly, tachycardia and an increased susceptibility to respiratory infections. Bacterial endocarditis is always more plausible in patent ductus arteriosus patients than the general population, therefore special attention must be paid to cardiology examination in case they develop a febrile disease [8].

The intellect can be normal or mild mental retardation can be demonstrated. Some patients have been described as having a "stocky" body build. Not all features need to be present at the same time in the same individual.

One study [3] proposed that patients can be divided into two subtypes: one that exhibits synophrys and wide eyebrows that have a "staircase" appearance in the lateral region and the other, containing individuals with underdeveloped eyebrows in the median area, that become increasingly thinner in the lateral portion.

Short Stature
  • Typical findings in the GCM syndrome are short stature, stocky body build, midface hypoplasia, small eyes, downslanting palpebral fissures, conductive hearing loss, highly arched and narrow palate, malocclusion, abnormally shaped teeth, oligodontia, microdontia[ncbi.nlm.nih.gov]
  • Short stature and growth retardation can be caused by the genetic mutation per se, by feeding impairment secondary to oral abnormalities or by heart failure secondary to the permeable arterial duct.[symptoma.com]
  • DOI: 10.1016/j.ajhg.2017.09.016 Resum: Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal[repositori.upf.edu]
  • Signs & Symptoms Gorlin-Chaudhry-Moss syndrome is characterized by a mild delay in physical development (growth retardation), short stature, mild mental retardation, and several physical abnormalities.[rarediseases.org]
  • stature, and intellectual disabilities) 759.89 Rud's (mental deficiency, epilepsy, and infantilism) 759.89 Russell (-Silver) (congenital hemihypertrophy and short stature) 759.89 Seckel's 759.89 sick Silver's (congenital hemihypertrophy and short stature[icd9data.com]
Coarctation of the Aorta
  • PDA commonly accompanies rubella syndrome and may be associated with other congenital defects, such as coarctation of the aorta, ventricular septal defect, and pulmonary and aortic stenoses.[checkorphan.org]
  • This method can also diagnose associated cardiac pathology, such as ventricular septal defect, coarctation of the aorta or pulmonary and aortic stenosis that often accompany a patent ductus arteriosus.[symptoma.com]
Congestive Heart Failure
  • In cases where congestive heart failure sets in, clinical examination can reveal dyspnea, cardiomegaly, tachycardia and an increased susceptibility to respiratory infections.[symptoma.com]
Dyspnea
  • This will initially cause exercise dyspnea that subsequently becomes permanent, fatigability, syncope, angina, cyanosis and signs of right heart failure.[symptoma.com]
Tooth Loss
  • Correct dental care is very important in order to prevent endocarditis and tooth loss.[symptoma.com]
  • Dental exam: A dental exam can be used to assess the condition of the teeth, important because individuals with GCM are prone to tooth loss.[health24.com]
Small Teeth
  • Affected individuals may also have farsightedness ( hyperopia ) and dental problems such as small teeth (microdontia) or fewer teeth than normal (hypodontia).[ghr.nlm.nih.gov]
Heart Failure
  • This will initially cause exercise dyspnea that subsequently becomes permanent, fatigability, syncope, angina, cyanosis and signs of right heart failure.[symptoma.com]
  • Those with heart failure require fluid restriction, diuretics, and cardiac glycosides to minimize or control symptoms. If these measures can’t control heart failure, surgery is necessary to ligate the ductus.[checkorphan.org]
Cyanosis
  • This causes the shunt to reverse; unoxygenated blood thus enters systemic circulation, causing cyanosis. PDA is found in 1 of every 2,500 to 5,000 infants and is the most common congenital heart defect found in adults.[checkorphan.org]
  • This will initially cause exercise dyspnea that subsequently becomes permanent, fatigability, syncope, angina, cyanosis and signs of right heart failure.[symptoma.com]
Tachycardia
  • In cases where congestive heart failure sets in, clinical examination can reveal dyspnea, cardiomegaly, tachycardia and an increased susceptibility to respiratory infections.[symptoma.com]
  • Affected infants may therefore exhibit an increased heart rate (tachycardia), enlargement of the heart (cardiomegaly), shortness of breath, and/or a failure to gain weight.[rarediseases.org]
Cardiomegaly
  • In cases where congestive heart failure sets in, clinical examination can reveal dyspnea, cardiomegaly, tachycardia and an increased susceptibility to respiratory infections.[symptoma.com]
  • Affected infants may therefore exhibit an increased heart rate (tachycardia), enlargement of the heart (cardiomegaly), shortness of breath, and/or a failure to gain weight.[rarediseases.org]
Continuous Murmur
  • Cardiac auscultation reveals a continuous murmur, more accentuated during systole, that extends during the diastole and has a crescendo/decrescendo character. During the first weeks of life, only the systolic component may be audible.[symptoma.com]
Small Eyes
  • Typical findings in the GCM syndrome are short stature, stocky body build, midface hypoplasia, small eyes, downslanting palpebral fissures, conductive hearing loss, highly arched and narrow palate, malocclusion, abnormally shaped teeth, oligodontia, microdontia[ncbi.nlm.nih.gov]
  • GCM syndrome symptoms include: Feet and metacarpal bones abnormalities Cognitive and hearing impairment Coarse hair and low hairline Underdeveloped mid-face Flattened forehead, nose and chin Small eyes Teeth abnormalities Learning disabilities Heart and[patientworthy.com]
  • Affected individuals also have distinctive facial characteristics that can include a flat or sunken appearance of the middle of the face ( midface hypoplasia ), and small eyes ( microphthalmia ) with narrowed openings (narrowed palpebral fissures).[ghr.nlm.nih.gov]
  • Symptoms - Gorlin Chaudhry Moss syndrome The list of signs and symptoms mentioned in various sources for Gorlin-Chaudhry-Moss Syndrome includes the 19 symptoms listed below: * Craniofacial dysostosis * Dental anomalies * Small eyes * Inability to open[checkorphan.org]
  • eyes (microphthalmia), absence of some teeth (hypodontia), and/or excessive amounts of hair (hypertrichosis) on most areas of the body.[hekim.org]
Fear
  • The most feared complication is the development of pulmonary hypertension due to the lack of closure of the patent ductus arteriosus.[symptoma.com]

Workup

The diagnosis of Gorlin-Chaudhry-Moss syndrome is established based on clinical examination, often immediately after birth, based on the typical clinical findings. Cardiac auscultation reveals a continuous murmur, more accentuated during systole, that extends during the diastole and has a crescendo/decrescendo character. During the first weeks of life, only the systolic component may be audible. However, this finding should be enough to point out the need for further evaluation, including a thoracic X-ray, an electrocardiogram and an echocardiogram.

The chest radiography may show anything from a normal aspect to modifications consistent with congestive heart failure: cardiomegaly based on the dilatation of the left heart, enlarged pulmonary arteries and veins and prominent ascending aorta. The electrocardiogram may show the presence of left or right ventricular hypertrophy and left atrial enlargement. The patent ductus arteriosus is best and more directly diagnosed by echocardiography, that shows high velocity jets of turbulent flow in the pulmonary artery, best seen in parasternal short axis view. This method can also diagnose associated cardiac pathology, such as ventricular septal defect, coarctation of the aorta or pulmonary and aortic stenosis that often accompany a patent ductus arteriosus. Even if the permeable duct is the only abnormality, periodical evaluation is necessary in order to detect the tendency towards developing pulmonary hypertension, at which point the abnormality cannot be operated on.

The physician should order conductive hearing loss tests, since this is one of the main traits of the syndrome. Better characterization of the bone defects can be obtained by ordering skull and extremities radiographs, showing the maxillary and phalangeal hypoplasia, the brachycephaly and the synostosis of the coronal suture. An ophthalmological examination is also imperative in order to reveal corneal scars, sclerocornea, astigmatism, ocular coloboma, and hyperopia, while a neurological examination can diagnose the presence of nystagmus. A gynecological exam may be necessary to characterize labia majora hypoplasia, while a dental consultation assesses tooth pathology.

Exome and genome sequencing can point out SLC25A24 gene aberrations and mitochondrial swelling in fibroblasts upon H2O2 exposure, demonstrating mitochondrial dysfunction while exposed to oxidative stress [9].

Right Ventricular Hypertrophy
  • The electrocardiogram may show the presence of left or right ventricular hypertrophy and left atrial enlargement.[symptoma.com]

Treatment

The treatment of Gorlin-Chaudhry-Moss syndrome is mostly symptomatic and supportive. A patent ductus arteriosus may close by itself if the child is born prematurely. In full term infants pharmacological closure may be attempted during the first days of life using intravenous indomethacin or ibuprofen lysine administration and in cases where this fails and pulmonary hypertension is likely to quickly develop, catheter occluder device implantation or surgical ligation is imperative. Surgery may also be necessary to correct craniofacial abnormalities, conductive hearing loss, umbilical hernia and visual impairment. Dental restoration is also important in order to facilitate nutrition and prevent speech impairment. Patients can also benefit from hearing aid devices, cochlear implants, corrective lenses or glasses, physical therapy and speech therapy [10]. All these interventions should be performed as soon as clinical condition allows, so the child can reach her full potential.

If heart failure develops, the patient should receive standard treatment, including cardiac glycosides, diuretics and fluid restriction.

Prognosis

The prognosis for this condition depends on whether or not complications set in. The most feared complication is the development of pulmonary hypertension due to the lack of closure of the patent ductus arteriosus. This will initially cause exercise dyspnea that subsequently becomes permanent, fatigability, syncope, angina, cyanosis and signs of right heart failure. When pulmonary hypertension sets in, the prognosis becomes grim because the underlying abnormality cannot be operated on any longer.

Visual prognosis also rests upon complication emergence. Farsightedness and astigmatism decrease visual accuracy even more, but corrective measures can be applied in this case.

Etiology

The etiology of Gorlin-Chaudhry-Moss syndrome is difficult to establish because of the paucity of affected individuals, with only seven cases ever published worldwide. However, the disease is considered by some to be transmitted in an autosomal recessive manner [1] and by others to be caused by a de novo X-linked dominant abnormality [3]. Maternal gonadal mosaicism for genetic mutations is another possibility [7]. The fact that all known cases were females leads to the hypothesis that inflicted males are stillborn or pregnancy stops evolving during the embryonic or early fetal phases. Two carriers of the diseased gene will have a 25% chance of having a homozygous dominant or homozygous recessive child and 50% chance for a heterozygous offspring, so the chance of the child not exhibiting any symptoms is 75%. The only known risk factor for this condition is the existence of the disease inside the family.

Recent advances in the study of this condition [9] have identified recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in gene SLC25A24 in five unrelated patients.

Epidemiology

The first case of Gorlin-Chaudhry-Moss was reported by Gorlin in 1960. Almost 60 years later, literature is only richer with 6 more reported entities, all female, making epidemiological data very scarce. No parental consanguinity was noted in any of the patients.

Sex distribution
Age distribution

Pathophysiology

SLC25A24 gene, believed to be responsible for this condition [9] encodes calcium-binding mitochondrial carrier protein SCaMC-1, a mitochondrial inner membrane ATP-Mg/Pi carrier. Affected fibroblasts mitochondria have been shown to swell after being treated with hydrogen peroxide, proving increased mitochondrial dysfunction when exposed to oxidative stress. Authors believe the SLC25A24 mutation is the cause of the connective tissue and skeletal abnormalities.

Prevention

Primary prevention of any genetic condition refers to the genetic counseling. If the disease is known to be present in the family history, future patients should seek genetic testing before conceiving. If a pregnancy is already evolving, fetal molecular testing is an option.

Secondary prevention relegates to forestalling complications. Any Gorlin-Chaudhry-Moss syndrome patient should receive an initial cardiology examination to establish whether a patent ductus arteriosus is present or not. In case the abnormality does exist, periodical controls are needed in order to establish the optimum time for surgical closure intervention. Keeping in mind that any congenital heart malformation patient is susceptible to develop bacterial endocarditis, the physician should order prophylaxis using the appropriate antibiotic prior to any procedure that bares a risk for bacteremia. In case endocarditis does develop, urgent and aggressive antibiotic treatment is a must. Correct dental care is very important in order to prevent endocarditis and tooth loss.

Summary

Gorlin-Chaudhry-Moss syndrome is a very rare congenital disease that seems to be caused by a defect of SLC25A24 gene resulting in multiple bone defects, accompanied by nail, hair, dental, visual, acoustic and cardiac abnormalities. The diagnosis is mostly clinical, but tests such as echocardiogram, radiographies and electrocardiograms can help establish it. Because many genetic diseases have overlapping traits with this syndrome, gene analysis is needed in order to be certain. Treatment is often needed for the patent ductus arteriosus, visual and hearing difficulties or umbilical hernia and should be tailored for every individual case.

Patient Information

Gorlin-Chaudhry-Moss syndrome is a very rare congenital disease, meaning that its manifestations are visible from birth. Affected children have bone abnormalities like short fingers and toes. The suture between cranial bones will close prematurely, causing the head to grow into an unusual shape. Excessive hair is present all over the body. When teeth emerge, dental abnormalities regarding number, shape and position are noticed. The inferior jaw, eyes and ears are small and several other facial particularities can be seen. A permeable arterial duct is often present, meaning that there is a connection between the two main arteries of the body: the aorta and the pulmonary artery. This can lead to heart failure and pulmonary hypertension during the childhood. There is speech, visual and hearing impairment, the labia majora can be underdeveloped and abdominal hernias can be sometimes noticed. The stature is short and the body build is stocky. The intelligence is normal or mildly decreased. Most of these abnormalities can be addressed via surgery, but the genetic defect cannot be repaired.

This disease is transmitted from parents to children and the only way to prevent it is to ask advice from a genetician if there is a case of Gorlin-Chaudhry-Moss syndrome in your family.

References

Article

  1. Gorlin RJ, Chaundry AP, Moss ML. et al. Craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies–a new syndrome? J Pediat. 1960;56:778-85.
  2. Ippel PF, Gorlin RJ, Lenz W, van Doorne JM, Bijlsma JB. Craniofacial dysostosis, hypertrichosis, genital hypoplasia, ocular, dental, and digital defects: confirmation of the Gorlin-Chaudhry-Moss syndrome. Am J Med Genet. 1992;44(4):518-22.
  3. Rosti R, KaraerK, Karaman B, Torun D, Guran S, Bahce M. Gorlin-Chaudhry-Moss syndrome revisited: expanding the phenotype. Am. J. Med. Genet. 2013;161A: 1737-42.
  4. Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:549-50.
  5. Preis S, Kaewel EV, Majewski F. Gorlin-Chaudhry-Moss or Saethre-Chotzen syndrome? Clin Genet. 1995;47(5):267-9.
  6. Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:548-49, 808.
  7. Aravena T, Passalacqua C, Pizarro O, Aracena M. Two sisters resembling Gorlin-Chaudhry-Moss syndrome. Am. J. Med. Genet. 2011;155A: 2552-5.
  8. Braunwald E, ed. Heart Disease. A Textbook of Cardiovascular Medicine. 3rd ed. Philadelphia, PA: W. B. Saunders Company; 1988:906-7.
  9. Ehmke N , Graul-Neumann L, Smorag L, et al. De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction. The American Journal of Human Genetics. 2017;101(5):833–43.
  10. Ieshima A. Gorlin-Chaudhry-Moss syndrome. Ryoikibetsu Shokogun Shirizu. 2001;33:765-6.

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Last updated: 2019-07-11 20:16