Perrault syndrome with amenorrhea, infertility, Tarlov cyst, and degenerative disc.

Perrault syndrome is a rare autosomal recessive disorder that affects both males and females. The syndrome causes deafness in males, however females display gonadal dysgenesis along with sensorineural hearing loss. Herein, we present a 27-year-old female patient who is deaf and mute along with primary amenorrhea. Hormonal assays revealed hypergonadotropic hypogonadism and the karyotype was 46 XX. Pelvic ultrasound described a hypoplastic uterus and streak ovaries. MRI of the spine showed degenerative discs and Tarlov cysts. Whole exome sequencing identified a LARS2 mutation and the patient was diagnosed with Perrault syndrome type four (PRLTS4).

Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms.

Perrault syndrome represents a genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females. Causative genes include HARS2, HSD17B4, CLPP, C10orf2, and LARS2. Some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 and are clinically separate from those without neurological symptoms other than a hearing loss (type 1). To date, all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Here, we report female siblings with biallelic mutations in LARS2, p.Glu294Lys, and p.Thr519Met, who were classified as type 2. The proposita developed progressive sensorineural hearing loss at 18 months and pervasive developmental disorder at 8 years, with repetitive behavior, insistence on sameness, attention deficit, tic, irritability, and an ataxic gait. At age 15 years, she was diagnosed as having primary amenorrhea with elevated FSH and LH and a decreased estradiol; ultrasound and magnetic resonance imaging examinations revealed a small uterus and no detectable ovaries. The proposita's younger sister presented with neonatal sensorineural hearing loss and a mild delay in motor and speech development. She was diagnosed as having primary amenorrhea with endocrinologic and radiographic findings that were comparable to those of her sister. She had difficulty with reading comprehension, and had trouble with open-ended test questions at 12 years of age. We concluded that Perrault syndrome patients with LARS2 mutations are at risk for neurologic problems, despite previous notions otherwise.

Rare cases of disorders of sex development (DSD) in adolescents with female phenotype.

BACKGROUND: Disorders of sex development (DSD) belong to uncommon pathologies; in addition, there are especially rare forms, such are ovotesticular disorders (OT), Turner syndrome and early malignisation of intraabdominal located gonads in the cases of androgen insensitivity syndrome. OBJECTIVE: In this article we present four rare cases of DSD in female phenotype adolescents: two cases of ovotesticular DSD with 46,XX and 46,XY karyotypes; one familial case of androgen insensitivity syndrome (AIS) with early malignancy (19-year-old) of intra-abdominally-located testicle in older siblings, and a case of spontaneous menstruation in a patient with Turner syndrome and mosaic karyotype 45,X/47,XXX. Rare cases of DSD are connected with diagnostic and management difficulties and so description of each such case and collection of data in this field is very important from a scientific, as well as a practical, point of view. Determination of prognosis and adequate management of each individual patient are also essential. Study of this issue is especially sensitive in the case of adolescent patients in order to avoid physiological stress, to reduce health risks and to improve quality of life.

Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals.

There have been considerable advances concerning understanding of the early and later stages of ovarian development; a number of genes have been implicated and their mutations have been associated with developmental abnormalities. The most important genes controlling the initial phase of gonadal development, identical in females and males, are Wilms' tumor suppressor 1 (WT1) and steroidogenic factor 1 (SF1). Four genes are likely to be involved in the subsequent stages of ovarian development (WNT4, DAX1, FOXL2 and RSPO1), but none is yet proven to be the ovarian determining factor. Changes in nomenclature and classification were recently proposed in order to incorporate genetic advances and substitute gender-based diagnostic labels in terminology. The term "disorders of sex development" (DSD) is proposed to substitute the previous term "intersex disorders". Three main categories have been used to describe DSD in the 46,XX individual: 1) disorders of gonadal (ovarian) development: ovotesticular DSD, previously named true hermaphroditism, testicular DSD, previously named XX males, and gonadal dysgenesis; 2) disorders related to androgen excess (congenital adrenal hyperplasia, aromatase deficiency and P450 oxidoreductase deficiency); and 3) other rare disorders. In this mini-review, recent advances concerning development of the genital system in 46,XX individuals and related abnormalities are discussed. Basic embryology of the ovary and molecular pathways determining ovarian development are reviewed, focusing on mutations disrupting normal ovarian development. Disorders of sex development according to the revised nomenclature and classification in 46,XX individuals are summarized, including genetic progress in the field.

P450c17 deficiency: clinical and molecular characterization of six patients.

CONTEXT: The characteristics of P450c17 deficiency include 46,XY disorder of sex development, hypertension, hypokalemia, and lack of pubertal development. OBJECTIVE: To better understand this rare enzymatic deficiency, we analyzed the CYP17A1 gene in six affected patients. DESIGN AND PATIENTS: We examined six patients, five 46,XY, and one 46,XX (age 9-29 yr) with complete lack of masculinization (female infantile external genitalia, no uterus) and delayed puberty, respectively, and different degrees of hypertension. MAIN OUTCOME MEASUREMENTS: Genotype-phenotype correlation was measured. RESULTS: Four homozygote mutations were identified by direct sequencing of the CYP17A1 gene corresponding to an alanin 302-proline (A302P) exchange; the loss of lysine 327 (K327del); the deletion of glutamate 331 (E331del); and the replacement of arginine 416 with a histidine (R416H). Both P450c17 activities were abolished in all the mutant proteins, except one, when expressed in COS1 cells. The E331del-mutated P450c17 retained 17alpha-hydroxylase activity. The mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of P450c17 proteins. CONCLUSION: These studies confirm lack of masculinization in 46,XY individuals as the pathognomic sign of the complete P450c17 deficiency. In XX individuals P450c17 deficiency should be considered in cases of delayed puberty. Age of onset and the severity of hypertension do not seem to be constant. Careful examination of long-term follow-ups in two of our patients suggested to us that estrogen treatment in P450c17-deficient patients might worsen the enzymatic defect, leading to aggravation of the hypertension.

Three new 46,XX male patients: a clinical, cytogenetic and molecular analysis.

BACKGROUND: XX males range phenotypically from completely masculinised individuals to true hermaphrodites and include a subset of SRY negative patients. The correlation between genotype (SRY+/-) and phenotype is still unclear. AIM: To report three new patients with this rare condition, one of whom was diagnosed prenatally and another was SRY negative, and to verify in our patients whether the presence of SRY results in a more masculinised phenotype. PATIENTS AND METHODS: We present two phenotypically normal XX male patients (10 and 13.5 years) and one 3.1 years old XX male with ambiguous external male genitalia Prader IV. The patients were diagnosed by clinical, hormonal, sonographic, genetic and histological criteria. RESULTS: Basal hormonal status was normal for phenotype but an excessive response to GnRH testing was noticed in the second patient together with insufficient hCG stimulation in all three patients. Pelvic ultrasound displayed male structures without Müllerian ducts; testicular biopsy, performed only in the intersex patient, showed Sertoli and Leydig cell hypoplasia. Chromosome analysis confirmed 46,XX karyotype. FISH analysis and molecular analysis by PCR were positive for Yp fragments/SRY gene on Xp in two patients and negative in the patient with ambiguous external genitalia. CONCLUSIONS: In our observation Y chromosome-specific material containing the SRY gene translocated to the X chromosome results in a completely masculinised phenotype. In the intersex patient, incomplete masculinisation without SRY suggests a mutation of one or more downstream non-Y testis-determining genes.