Detection Rates Table

25-50% of cases with holoprosencephaly (HPE) have abnormal karyotypes, the vast majority of which are detectable by SignatureChip®.

15-20% of HPE cases with normal chromosomes will have sequence mutations in SHH, ZIC2, SIX3, or TGIF. Sequence mutations are not detectable by array CGH. A negative array CGH test result does not exclude the possibility that one or more of these genes may play a role in the subject's phenotype.

4.7% of chromosomally normal and mutation-analysis normal HPE cases have microdeletions in SHH, ZIC2, SIX3 or TGIF (Bendavid et al. 2006. Hum Genet 119:1-8. Medline). The majority of reported microdeletions are detectable by SignatureChip®.

PTEN Hamartoma Tumor Syndrome is a syndrome that incorporates several disorders with phenotypic overlap caused by mutations in PTEN, including Bannayan-Riley Ruvalcaba syndrome, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome. While these disorders have specific distinguishing characteristics, they have features in common and recommended management is virtually identical for all.

2-11% of cases of Bannayan-Riley-Ruvalcaba syndrome (BRRS) are caused by deletions of the PTEN gene, the majority of which are detectable by array CGH technology. Approximately 60% have identifiable PTEN point mutations. Subjects with this condition often have autistic features, macrocephaly, hamartomatous intestinal polyps, lipomas and penile freckling.

~1% of Cowden syndrome (CS) are caused by deletions of the PTEN gene, the majority of which are detectable by array CGH technology. Approximately 80% have identifiable PTEN point mutations that are not detectable by array CGH. Subjects with this condition may have cancers of the breast, uterus, thyroid, and urogenital tract as well as macrocephaly, Lhermitte-Duclos disease (macrocephaly, seizures, and mental retardation associated with dysplastic gangliocytoma of the cerebellum), specific skin lesions (e.g., trichelemmomas, lipomas), hamartomatous polyps, fibrocystic breasts, and urogenital system malformations and tumors. Autistic-like tendencies have also been reported in some patients.

No large deletions have been reported in cases of Proteus syndrome or Proteus-like syndrome. However, this disorder has phenotypic overlap with BRRS and CS and is considered part of the PTEN Hamartoma Tumor Syndrome Spectrum. Detection rates for point mutations are not reported consistently, implying a possible second locus for these syndromes. These are disorders of mosaic, progressive overgrowth, including connective tissue nevi, macrocephaly, ovarian and parotid tumors, atypical adipose tissue growth, and vascular malformations.

While Macrocephaly/autism syndrome is not considered part of the PTEN Hamartoma Tumor Syndrome, it is allelic to these tumor syndromes and has the overlapping phenotype of both macrocephaly and autistic-like features. Approximately 4% of patients with a head circumference >2 standard deviations above the mean and autism spectrum disorder have point mutations in PTEN, that are not detectable by array CGH.

The sex determining region (SRY) gene is located on Yp11.31. Dosage abnormalities of SRY (i.e. loss of SRY on the Y chromosome or presence of SRY on other chromosomes) are responsible for disorders of sexual differentiation., such as XX male syndrome and XY gonadal dysgenesis.

XX male syndrome: XX karyotype with male phenotype (external genitalia normal to ambiguous, normal testicles, azoospermia, lacking internal female structures).

80% of XX males have SRY. Typically, XX males with SRY have normal external genitalia and develop gynecomastia around the time of puberty. Presence of SRY on an X chromosome is typically due to interchange between pseudoautosomal regions on the X and Y p-arms.

20% of XX males have no SRY. Typically, XX males with no SRY have some level of genital ambiguity and are more likely to have gynecomastia prior to puberty. The cause of masculinization in these individuals is not well understood. Explanations for some cases may include: low level XX/XY or XX/XXY mosaicism which is known to cause overlapping features, SOX9 duplication on chromosome 17q (one case has been reported; Medline), or autosomal recessive inheritance (one large family has been reported; Medline).

XY females: XY karyotype with female phenotype (range of normal primary and secondary sexual characteristics, defined by individual syndrome).

Loss of SRY on the Y chromosome causes XY gonadal dysgenesis, also called Swyer syndrome, causing failure of pubertal development, lack of external secondary sexual characteristics, and streak gonads internally with an increased risk for gonadoblastoma.  Expressivity in families is variable.

10-15% of females with XY gonadal dysgenesis have a deletion of SRY, while an additional 10-15% have an SRY point mutation.  Females with XY gonadal dysgenesis and no SRY abnormalities may have mutations in other genes, such as deletion of the DMRT1 and/or DMRT2 genes on chromosome 9p which has been rarely reported (Medline), but other etiologies are not well known.

XY females with other phenotypes include Androgen insensitivity syndrome (AIS), caused by mutations in the androgen receptor gene, as well as disorders causing extragonadal defects in addition to the female phenotype, such as Campomelic dysplasia.