CLINICAL REPORT
Gorlin–Chaudhry–Moss Syndrome Revisited: Expanding the Phenotype Rasim O. Rosti,1* Kadri Karaer,1 Birsen Karaman,2 Deniz Torun,1 Sefik Guran,3 and Muhterem Bahce1 1
DepartmentQ1of Medical Genetics, Gulhane Military Medical Academy, Ankara, Turkey 2 Istanbul Medical Faculty, Department of Medical Genetics, Istanbul University, Istanbul, Turkey 3
Department of Medical Biology, Gulhane Military Medical Academy, Ankara, Turkey
Manuscript Received: 25 October 2012; Manuscript Accepted: 9 March 2013
Gorlin–Chaudhry–Moss syndrome (OMIM 233500) is a rare congenital malformation syndrome with the cardinal manifestations of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, ocular, and dental anomalies. Since 1960, only six affected individuals have been reported. We report a 4-year and 6-month-old female patient with this phenotype and review the clinical presentation of all patients known so far. Previously unreported malformations of the extremities, larynx, and nose are also described, expanding the phenotype of this rare syndrome. Array-CGH analysis did not show pathological deletions or duplications. Ó 2013 Wiley Periodicals, Inc.
Key words: Gorlin–Chaudhry–Moss syndrome; craniofacial dysostosis; extremities; lower; extremities; upper; bifid nose; syndrome delineation
INTRODUCTION Gorlin–Chaudhry–Moss (GCM) syndrome is a rare clinical entity first reported in 1960 [Gorlin et al., 1960]. Only six patients have been reported to date. The patients share clinical findings of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, and ocular and dental anomalies [Aravena et al., 2011]. We recently evaluated a seventh patient with the typical findings and other unreported malformations.
CLINICAL REPORT The patient was born at term to unrelated healthy parents after an uneventful pregnancy. The parents had two spontaneous abortions. Her birth measurements are unknown. Multiple congenital anomalies were noted at birth. She was operated on due to coronal craniosynostosis at 18 months of age. She had laryngomalacia that became asymptomatic by the age of 3 years. At 4.5 years of age she was referred to Gulhane Military Medical Academy Medical Genetics Department due to dysmorphic features and the parents wish for a new pregnancy. Psychomotor development was within normal limits. Height was 101 cm (3rd–10th centile), weight 18 kg (50th–75th centile), and OFC 48 cm (10th–25th centile). On her
Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Rosti RO, Karaer K, Karaman B, Torun D, Guran S, Bahce M. 2013. Gorlin– Chaudhry–Moss syndrome revisited: Expanding the phenotype. Am J Med Genet Part A 9999:1–6.
physical examination she had brachy/turricephaly, low posterior and anterior hairline, synophrys, upslanted palpebral fissures, inability to fully open or close her eyes, lateral flaring of eyebrows, long eyelashes, and bilateral upper eyelid colobomas. Underdeveloped ala nasi, prominent columella and bifid nasal tip, thin upper lip vermillion, narrow and high palate with a medial cleft of the soft palate, midface hypoplasia, and underdeveloped small ears with increased posterior angulation were also observed (Figs. 1–3). There was generalized hypertrichosis. Pectus excavatum, small thumbs, and index fingers with accompanying small nails, absent flexion crease of the thumbs, bilateral single transverse palmar creases, bilateral fifth finger clinodactyly, and bilateral cutaneous syndactyly of the second and third toes with small toenails were noted (Figs. 4–6). The labia majora were small. Ophthalmologic examination showed bilateral upper eyelid colobomas and hyperopia. Dental examination showed microdontia, irregularly shaped widely spaced teeth, oligodontia, narrow, and high arched palate with medial cleft. Audiological investigations showed bilateral mild conductive hearing loss (40 dB loss of left and right ear). Conflict of interest: none. Correspondence to: Rasim O. Rosti, M.D., Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, M/C 0665, LBR, Rm 481 La Jolla, CA 92093-0665. E-mail:
[email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2013 DOI 10.1002/ajmg.a.35954
AJMA-12-0880.R4(35954)
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. Frontal facial view of the patient. Synophrys, upslanted palpebral fissures, lateral flaring of eyebrows, long eyelashes, bilateral upper eyelid colobomas, underdeveloped ala nasi, prominent columella, bifid nasal tip, and full lips can be observed.
An X-ray of the left hand showed small distal phalanges of the first and second fingers and lateral skull X-ray showed premaxillary underdevelopment (Figs. 7 and 8). Denver developmental screening test revealed that the patient’s development was within normal limits. Abdominal ultrasonography, echocardiography and cranial magnetic resonance imaging were all normal. Chromosomal investigations showed a normal 46,XX karyotype. Array-CGH analysis (Roche, NimbleGen CGX-3, Basel, Switzerland) of the patient showed four copy number variants (CNVs). Among these, three CNVs overlapped with a polymorphism listed in the database of genomic variants (DGV) (http:// projects.tcag.ca/) for healthy individuals and were judged likely to
FIG. 3. Eyelid coloboma and configuration of the eyebrow.
be non-pathogenic. For the remaining genomic imbalance, CGH analysis was performed on the parents and it was seen that healthy father carried the 12q24.33 duplication in the heterozygous state. We concluded that this was a benign variation.
DISCUSSION Gorlin–Chaudhry–Moss (GCM) syndrome is a multiple congenital anomaly syndrome with only six patients reported to date. We have
FIG. 2. Lateral view. Low anterior hairline, lateral flaring of eyebrows, long eyelashes, full lips, small ears, with increased posterior angulation can be distinguished.
FIG. 4. Hands of the patient. Dorsal view. Small thumbs and index fingers with accompanying small nails and bilateral fifth finger clinodactyly is present.
ROSTI ET AL.
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FIG. 5. Hands of the patient. Plantar view. Absent flexion crease of the thumbs, bilateral single transverse palmar creases, bilateral fifth finger clinodactyly are observed.
listed the cardinal, common, and rare findings of the syndrome and delineate the phenotype (Table I). Analysis of the clinical data show that stocky body build, normal intelligence, craniosynostosis, conductive hearing loss, hyperopia and facial dysmorphism, dental anomalies, extremity anomalies, hypertrichosis, umbilical hernia, and genital underdevelopment are present in a majority of the patients and comprise the cardinal findings for the syndrome. Brachycephaly, low frontal hairline, coarse hair, midface hypoplasia, short palpebral fissures, microphthalmia, high arched narrow palate, and ears with increased posterior angulation constitute the dysmorphism that was present in all of the reported patients. The patient described here also has stocky body build, normal development, common orofacial, and systemic findings as well as
FIG. 6. Feet of the patient showing bilateral 2–3 toe cutaneous syndactyly.
FIG. 7. Hand X-ray showing hypoplastic distal phalanges of the first and second fingers.
FIG. 8. Lateral skull X-ray showing premaxillary underdevelopment.
þ þ þ Normal þ þ þ þ þ þ
þ þ þ Normal þ þ þ þ þ þ
Aplastic nails
Cutaneous syndactyly
Small finger (seen on examination)
Ectropion of lower eyelid Increased posterior angulation of ears Somatic growth and performance Stocky body build Psychosocial motor abilities Systemic findings Coronal craniosynostosis Hypertrichosis Hyperopia Conductive hearing loss Dental anomalies Extremities Hypoplastic distal phalanges (hand and feet) Small nails
þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ
Orofacial findings Brachycephaly Coarse hair Low frontal hairline Midface hypoplasia Synophyris Depressed supraorbital ridges Downslanted palpebral fissures Short palpebral fissures Upper eye lid clefts Microphthalmia Prominent columella Bifid nasal tip High arched narrow palate
Gorlin et al. Patient #1 Patient #2
Right 2–3 (finger) Bilateral 2–3 (toe)
þ
þ þ þ þ
þ Normal
þ þ þ þ þ þ þa þ þ þ (Small medial cleft, bifid uvula) þ
Bilateral fourth (finger) Bilateral fifth (finger), fourth and fifth (toe)
þ
þ þ þ þ þ
þ Normal
þ
þ þ þ þ þ þ þ þ þ þ
Ippel et al. Patient #3 Patient #4
TABLE I. ClinicalQ2 Manifestations
N/A
þ
þ
Right 4–5 (toe)
þ
þ N/A N/A
þ
þ þ
þ þ þ þ þ þ þ þ þ N/A
þ
þ N/A N/A
N/A
N/A N/A
þ þ þ þ þ þ þ þ þ þ (Submucosal cleft)
Aravena et al. Patient #5 Patient #6
Bilateral 1st and 2nd (finger)
Bilateral 2–3 (toe)
Bilateral first and second (finger)
þ
þ þ þ þ þ
þ Normal
þ
þ þ þ þ þ Upslanting þ þa þ þ þ þ (Small medial cleft)
Our patient
4 AMERICAN JOURNAL OF MEDICAL GENETICS PART A t-
ROSTI ET AL.
þ þ þ (PDA) þ þ þ (Internal) N/A, not available. a Coloboma.
þ (PDA) þ þ (External) Single transverse palmar creases Laryngomalacia Congenital heart disease Umbilical hernia Genital hypoplasia
þ (PDA) þ þ (External)
þ (External)
Absent flexion creases
Ippel et al. Patient #3 Patient #4 Gorlin et al. Patient #1 Patient #2
TABLE I. (Continued )
Aravena et al. Patient #5 Patient #6
Our patient Bilateral finger thumb Bilateral þ þ (External)
5 he extremity findings that most of the patients show (Table I). She also has an upslanted palpebral fissure compared to the downslanted palpebral fissures of the other patients, which may change the typical gestalt. The authors propose that this is a familial trait since both parents of the patient carried this palpebral orientation. Dental anomalies were emphasized in previous reports and orodental findings including large alveolar processes, malocclusion, oligodontia, microdontia, “bell-shaped” dental crowns, “spindleshaped” roots and small/missing pulp chambers were found in nearly all patients [Ippel et al., 1992]. Large alveolar processes, malocclusion, oligodontia, and microdontia were also reported in our patient. The new expanding extremity findings of the syndrome also merit discussion. Underdeveloped distal phalanges of hand and feet were reported in all patients and was the only common finding [Gorlin et al., 1960; Ippel et al., 1992]. Other features such as small nails and cutaneous syndactyly were reported in three patients. Our patient also has bilateral small nails of the thumb and second finger and bilateral cutaneous syndactyly of the second and third toes. The patient also had some features that were not reported previously. These include upslanted palpebral fissures, bifid nasal tip, small fingers (bilateral thumb and second finger), absent flexion crease of the thumbs, bilateral single transverse palmar creases, and laryngomalacia. These findings have to be substantiated by other patients to be included in the phenotypic spectrum of the disorder. The first patient of Ippel et al. [1992], the patients reported by Aravena et al. [2011] and the present patient (which we designate as group A) share some characteristic findings and a typical gestalt that are not seen in three other patients (group B). The primary distinction was the eyebrow morphology. These patients had synophyrs and a laterally widening and extending hair pattern that forms a “stair case” descending to the lateral orbital rim and canthus. The group B patients had an underdeveloped medial part, a well developed middle part, and a gradually thinning lateral part of the eyebrow. Moreover, the group of patients that include the present patient had prominent columella and relatively underdeveloped ala nasi that differed from the group B patients. The present patient also had a bifid nasal tip. It appears that the first patient of Ippel et al. [1992] may have had a bifid nasal tip (deduced from the photograph). Group A patients also did not seem to have the deeply set eyes that Group B patients had and had better developed lateral parts of the supra orbital ridges. Altogether, these features make up a different mid-face pattern that produces a distinct gestalt. The group A patients also shared small medial clefts of the palate and cutaneous syndactyly that were not encountered in Group B patients. Patient 1 of Ippel et al. [1992] had a bifid uvula that was not noted in other patients. We conclude that there are two subgroups within this syndromic complex that have both common and distinct clinical findings that affect the gestalt, which is a good diagnostic handle for dysmorphologists. As the number of patients increase and molecular etiology of the disorder is determined, it will be determined if Group A and B represent different phenotypic presentations of the same molecular entity or distinct molecular entities with significant clinical overlap. All the patients reported to date have been female with no known parental consanguinity. As the original patients reported by Gorlin et al. [1960] were siblings born to unaffected parents the condition
6 is considered to be inherited in an autosomal recessive manner. However, the lack of consanguinity in a disorder that is so rarely encountered combined with the fact that all affected patients are female could suggest a de novo X-linked dominant disorder with male lethality. In this case, the mothers of the patients of Gorlin et al. [1960] and Aravena et al. [2011] may have gonadal mosaicism for the causative mutation. As more patients are reported, the mode of inheritance for this disorder will be clarified. Patient 2 of Ippel et al. [1992] was reported as being involuntarily childless. She had irregular menstrual cycles, a short vagina, and a small uterus. The follow up information of the original patients did not include their reproductive histories. We also have no information about patient 1 of Ippel et al. [1992] who may likely be in her third decade at this writing. This information on fertility could be important in establishing recurrence risks. Additionally, an accompanying infertility aspect of the syndrome complex could account for the rare incidence. Since the a-CGH analysis of the patient described here was negative, we propose that the mutation responsible for the syndrome is either a point mutation or a small copy number variation that was not detected by a-CGH. A family with one affected individual may be given an estimated gonadal mosaicism recurrence rate considering the syndrome as a X-linked dominant disorder with male lethality. There are other syndromes that have overlapping features with Gorlin–Chaudhry–Moss syndrome and should be considered in the differential diagnosis. One is Petty syndrome (OMIM 612289), a congenital progeroid syndrome with pre- and post-natal growth restriction, decreased subcutaneous fat with loose skin, coronal synostosis, unruly hair pattern, thick eyebrows, and normal or near normal development [Petty et al., 1990]. Although the present patient shared some findings with Petty syndrome such as coronal synostosis, extremity anomalies, and some orofacial findings, she did not have decreased subcutaneous fat with loose skin or unruly hair pattern and had extra findings (such as prominent hypertrichosis, conductive hearing loss) that patients with Petty syndrome do not exhibit but are common in Gorlin–Chaudhry–Moss syndrome. Another syndrome that is mentioned alongside Gorlin–
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chaudhry–Moss syndrome is Saethre–Chotzen syndrome. In a recent report, a female patient was considered to have features reminiscent of Gorlin–Chaudhry–Moss syndrome [Preis et al., 1995]. That patient clearly lacked the hypertrichosis, hearing loss, the striking eyebrow pattern and the picture is more similar to Saethre–Chotzen phenotype. This patient also has coronal and metopic synostosis, which has not been reported in Gorlin– Chaudhry–Moss syndrome but is reported in patients with Saethre–Chotzen. In conclusion, we report the seventh case of Gorlin–Chaudhry– Moss syndrome and review the clinical presentations of the previously published patients in order to ascertain the cardinal, common, and uncommon findings of the disorder. We report a set of hitherto unencountered findings of laryngomalacia, extremity, and nasal findings that may expand the phenotype of the syndrome. Certain extremity anomalies that were present in the patient reported here suggest that these features can be added to the clinical synopsis of the disorder now that they are found in more than one patient. We have also discussed possible subgrouping, inheritance model, and the fertility aspect of the syndrome.
REFERENCES Aravena T, Passalacqua C, Pizarro O, Aracena M. 2011. Two sisters resembling Gorlin–Chaudhry–Moss syndrome. Am J Med Genet Part A 155A:2552–2555. Gorlin RJ, Chaudhry AP, Moss ML. 1960. Craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies-A new syndrome? J Pediatr 56:778–785. Ippel PF, Gorlin RJ, Lenz W, van Doorne JM, Bijlsma JB. 1992. Craniofacial dysostosis, hypertrichosis, genital hypoplasia, ocular, dental, and digital defects: Confirmation of the Gorlin–Chaudhry–Moss syndrome. AmQ3 J Med Genet 44:518–522. Petty M, Laxova R, Wiedemann H. 1990. Previously unrecognized congenital progeroid disorder. AmQ4 J Med Genet 35:383–387. Preis S, Kaewel EV, Majewski F. 1995. Gorlin–Chaudhry–Moss or Saethre– Chotzen syndrome? Clin Genet 47:267–269.
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