Journal of Cleft Lip Palate and Craniofacial Anomalies

: 2017  |  Volume : 4  |  Issue : 1  |  Page : 77--79

Commentary on cleft palate associated with Turner's syndrome and anterior cervical hypertrichosis

Richie Gupta1, Seema Thakur2,  
1 Department of Plastic, Cosmetic and Reconstructive Surgery, Fortis Hospital, New Delhi, India
2 Department of Plastic, Genetics and Foetal Medicine, Fortis Hospital, New Delhi, India

Correspondence Address:
Richie Gupta
A1/11, Jiwan Jyoti Apartments, Pitampura, New Delhi - 110 034

How to cite this article:
Gupta R, Thakur S. Commentary on cleft palate associated with Turner's syndrome and anterior cervical hypertrichosis.J Cleft Lip Palate Craniofac Anomal 2017;4:77-79

How to cite this URL:
Gupta R, Thakur S. Commentary on cleft palate associated with Turner's syndrome and anterior cervical hypertrichosis. J Cleft Lip Palate Craniofac Anomal [serial online] 2017 [cited 2020 Sep 26 ];4:77-79
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Turner syndrome (TS) is one of the common chromosomal anomalies, occurring in humans, with an incidence of around 1 in 2500. It is an important cause of short stature and ovarian insufficiency in females, and it is caused by loss of part or whole chromosome X. The phenotype consists of short stature (average 20 cm below normal), ovarian dysgenesis, neck webbing, congenital peripheral lymphedema, cubitus valgus, and widely spaced nipples (shield chest) with poor breast development. There may be also defects in cardiovascular system (left-sided cardiac anomalies such as coarctation of aorta and aortic valve defects), endocrine (impaired carbohydrate and lipid metabolism, autoimmune thyroiditis),[1] renal (horseshoe kidney, double collecting system), hearing (conductive hearing loss in infancy and sensorineural hearing loss in adolescence), and neurologic defects (brain changes consistent with reduced psychosocial abilities and visuo-spatial numerical processing).[2] Head and neck abnormalities include pterygium coli, flattening of skull base, reduced transverse maxillary dimension, retrusion of both jaws, epicanthic fold, ptosis of eyelid, prominent/low set ears, and low hairline. Bones (shortened fourth metacarpal) and joint lesions (wide carrying angle) are seen. Pigmented skin nevi and dysplastic nails may also be present.[3] In oral cavity, narrow- and high-arched palate, premature tooth eruption, increased molarization of premolars, reduced cusp height and crown size, and decreased enamel could be associated.[4]

The wide variation in phenotype is due to the fact that TS consists of a heterogeneous group of disorders. It was classically thought that there is deletion of an X-chromosome during meiosis, leading to a 45, X genotype, validated by karyotyping. With advances in DNA analysis, using fluorescent techniques and next-generation sequencing (NGS), and then carrying out genome-wide association studies, it is now known that most cases of Turner phenotype may be mosaics. It is now thought that a true 45, X genotype may be incompatible with survival. There are some estimates that TS affects around 3% of all females conceived,[3] but a high spontaneous abortion rate (99.9%)[5] leads to an incidence of around 1:2500 live births. Increase in the sensitivity of genetic techniques is gradually leading to the identification of more mosaics and lower level of mosaicism.

The present methods indicate that 40%–60% of patients with TS may be mosaics having X/XX, X/Xi (Xq), X/XXX, X/XX/XXX, XY, nonmosaics Xi(Xq), X(del(Xq)), isochromosome Xq, isochromosome Xp, ring X, and X/isodecentric X.[3],[5],[6] More copy number variations (CNVs) in this region will lead to more severe defects in phenotype, while lesser number of variants will lead to a mild disease. Loss of short stature homebox (SHOX) gene at Xp22.33 location results in short stature.[7] It is important to diagnose TS early, as early endocrine intervention with growth hormone (starting at the age of 2–5 years) and estrogens (starting at around 12 years of age) can result in the individual having nearly normal height and reproductive capacity, despite many CNVs.

Cleft palate occurs in around 1:2500 live births, with around half being syndromic and the other half being nonsyndromic. A genome-wide association analysis of cleft palate reveals a significant association with missense variant in GRHL3 location on chromosome 1 (1p36.11).[8] Cleft palate occurs with only slightly increased frequency in TS though the incidence of high-arched palate (ogival palate) approaches 100%.

Anterior cervical hypertrichosis (ACH) was first described by Trattner et al. in 1991.[9] Tsukahara and Kajii [10] in their series of seven cases spanning three generations reported the association with TS in one case. This patient's karyotype had isochromosome Xq unlike Trattner et al.[9] who thought their cases to have autosomal recessive transmission. Braddock (1995) believed ACH to be associated with older paternal age. Echeverría [11] conducted a study involving three cases spanning two generations which included a patient with Down's syndrome. Monteagudo in his review of 28 cases till 2009[12] and Megna in forty cases till 2015[13] found that ACH may be associated with neurologic disorders (peripheral neuropathy, mental retardation with developmental delay), ophthalmic disorders (optic atrophy, chorio and/or retinal disorders), hallux valgus, other forms of hypertrichosis, facial dysmorphism, and sensory/motor neuropathy.

The present case has coexistence of a TS-like phenotype, together with cleft of soft palate, ACH, and orbital dystopia, with karyotype 46, XX. Genetic testing should be performed to confirm the diagnosis of TS in any patient with the characteristic clinical features. The first step is a karyotype analysis, usually using peripheral blood mononuclear cells. To detect mosaicism, a minimum of thirty cells in metaphase should be scored, as recommended by the American College of Medical Genetics. If the initial karyotype is normal in a patient with a strong clinical suspicion of TS, a second karyotype should be performed using a different tissue such as the skin. This is because there are case reports of girls strongly suspected of having TS on clinical grounds who have a normal peripheral blood lymphocyte karyotype 46, XX, but a 45, X karyotype on analysis of skin fibroblasts. This phenomenon may be attributable to abnormal cell lines dying out with age in the bone marrow, leaving the normal cell line in the peripheral blood. In addition, mosaic karyotypes may be distributed differently among tissues in the same patient.

Furthermore, though the hypertrichosis is localized, was Y-chromosome material (which though may be absent in peripheral blood cells) may be found in fibroblasts and gonadal cells excluded by fluorescence in situ hybridization with DYZ3 locus probe? The TS patients, having part or whole of a Y-chromosome or an altered Y-chromosome in their karyotype, are at a high risk for developing gonadoblastoma (up to 33%) in their streak gonads, and thus may be candidates for prophylactic gonadectomy.[14]

The authors probably carried out a high-throughput NGS for selected regions on X-chromosomes. The coverage is mentioned in Xp11.22, Xp11.23, Xq24, and Xq28. Pyrosequencing test is based on the quantitative assessment of 18 markers on X-chromosome and one on Y-chromosome single nucleotide polymorphisms. This test appears to be both sensitive and specific for TS, but the ultimate clinical utility (and cost/benefit issues as well as ethical concerns) of this test requires further assessment. We feel that a microarray analysis for CNV analysis would have been ideal. Analysis of buccal smears for nuclear heterochromatin (Barr bodies) is an inaccurate and outmoded test and should not be used.

It has been hypothesized that the physical manifestations of TS are either due to the absence of two normal sex chromosomes before X-chromosome inactivation or to haploinsufficiency of genes in the pseudoautosomal regions of the X- or Y-chromosome, as well as to aneuploidy itself. Both the short- and the long-arm of the X-chromosome contain genes important for ovarian function, and aneuploidy alone may lead to a reduction in the number and survival of oocytes.[15]

Loss of interstitial or terminal Xq material can result in short stature and primary or secondary ovarian failure. In general, loss of Xp results in the full phenotype of TS. Very distal Xp deletions are compatible with, but do not ensure, normal ovarian function. Loss of this region usually confers short stature and the typical skeletal changes, in part as a result of haploinsufficiency of the SHOX gene, located in the pseudoautosomal region of Y and Xp. The SHOX gene is probably not the only gene responsible for the skeletal features. Aneuploidy itself may contribute to growth failure. Loss of the testis-determining factor (SRY) gene locus on the short arm of the Y-chromosome (e.g., 46, X, del(Yp)) also leads to the phenotype of TS, even without a 45, X cell population. A region on Xp11.4 has been proposed as critical for the development of lymphedema in these patients.

A mutation analysis of SHOX gene sited on Xp22.33 or Yp11.32 would have confirmed or ruled out Leri–Weill syndrome. In this syndrome, with a prevalence of 1:1000–2000, females are affected more severely and more often (4:1). Patients present variably with short stature; high-arched palate; mesomelic limb shortening; short, thick metacarpals; bowing of tibia; increased carrying angle; Madelung deformity; micrognathia; scoliosis; and calf hypertrophy. A wrist/forearm X-ray may have confirmed the typical deformity.[16],[17],[18],[19]

Noonan syndrome, with an incidence of 1:1000–2500, is also a possibility in this case. Patients with Noonan syndrome will have short stature and right-sided cardiac abnormalities. Noonan syndrome is genetically heterogenous and can be caused by mutations in PTPN11, SOS1, RAF1, NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL genes. This causes defects in RAS/activated protein kinase signaling pathways, and it is inherited in autosomal dominant manner. Patients present variably with short stature; learning problems; short, webbed neck; flat nasal bridge; scoliosis; pectus excavatum/carinatum; low hairline at the nape of neck and high hairline at the front of head; triangular face shape; hypertelorism; down slanting eyes; epicanthal folds; ptosis; proptosis; strabismus; nystagmus; low-set ears; micrognathia; high-arched palate; hearing loss; cubitus valgus; lymphedema of hands/feet; and pigmented nevi.[20],[21],[22]


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