A rare cause for primary amenorrhoea.

Gonadal (ovarian) dysgenesis with normal chromosomes (46, XX), XX female gonadal dysgenesis (XX-GD) is a rare genetically heterogeneous disorder. In 1951, Perrault reported the association of gonadal dysgenesis and deafness, now referred to as Perrault's syndrome. Perrault syndrome is a rare autosomal recessive condition affecting both females and males; only females have gonadal dysgenesis associated with sensorineural deafness, which is present in both sexes. We present a case of sporadic Perrault syndrome in a 35-year-old female with primary amenorrhea, sensorineural deafness, marfanoid features and normal karyotype. There are very few case reports describing the condition, even lesser reports of association with marfanoid habitus. We report this case for its rarity and add to the spectrum of the disease that remains undetermined.

INTRODUCTION

Primary amenorrhea is usually the result of a genetic or anatomic abnormality. In young women with primary amenorrhea, the single most common cause is primary ovarian failure due to gonadal dysgenesis. Primary ovarian failure with streak gonads is the main feature of female gonadal dysgenesis. It is commonly caused by X-chromosome aberrations such as in Turner syndrome, but individuals with a normal chromosome complement and ovarian dysgenesis also exist. We present such case with normal female sex chromosome constitution and hypergonadotropic hypogonadism

CASE REPORT

A 35-year-old female patient presented to our medical outpatient department with complaints of palpitation and chest pain of 6 months duration. Patient had paroxysmal episodes of palpitations that lasted few minutes, resolved spontaneously, and were not associated with exertion or other aggravating factors. Patient had chest pain that was retro-sternal, intermittent not related to exertion and resolved spontaneously. Frequency of patient's complaints had increased from 3 weeks prior to presentation. There was no history of significant medical illness in the past. She was born out of a non-consanguineous marriage. She had an elder brother. There is no history of significant medical illness in the family. Menstrual history revealed that she never attained Menarche. On examination she had dolicocephaly, arachnodactyly, high arched palate, she was tall statured [Height 165 cm; Figure 1], her arm span (176 cm) was more than her height, arachnodactyly [Figure 2], reduced upper to lower body segment ratio (0.83), and she had positive wrist and thumb sign. Patient had underdeveloped rudimentary breasts (Tanner stage 2), sparse pubic hair (Tanner stage 1), and absent axillary hair. She had normal external genitalia. Her vitals were normal. Cardiovascular examination revealed mid-systolic click with a late systolic murmur, other systems were essentially normal. Blood investigations showed normal hemogram. Her blood glucose, renal function tests, liver function tests, and serum electrolytes were within normal limits. Ultrasonogram of abdomen and pelvis showed atrophic uterus and streak ovaries. Echocardiogram ECHO/Doppler revealed prolapse of anterior mitral leaflet, mitral regurgitation and normal left ventricular systolic function. Patient was further evaluated for possible causes of primary amenorrhea [Table 1]. She had low levels of estrogen (Estradiol-10 pg/mL; normal 15-200 pg/mL), serum testosterone (0.16 pg/mL, normal 0.6-6.8 pg/mL), and progesterone (0.56 ng/mL). She had elevated levels of gonodotropins, follicle-stimulating hormone (FSH) (101.3 IU/L), and luteinizing hormone (LH) (31.6 IU/L). Serum prolactin (12 ng/mL, normal 0-20 ng/mL) and thyroid function tests (Free T4-9.2 mcg/dL, normal 4.6 to 11.2 mcg/dL; TSH-3.49mU/L, normal 0.4-5.0 mU/L) were normal. Her karyotype was normal (46 XX). She was diagnosed with primary gonadal (ovarian) dysgenesis with marfanoid features. Further audiometric evidence of mild bilateral sensorineural deafness completed the diagnosis of Perrault syndrome.

Figure 1

Marfanoid habitus: Tall stature, height 165 cm; arm span to height ratio of 1.067; upper segment to lower segment ratio of 0.83

Figure 2

Arachnodactyly with high metacarpal index MCI

Table 1

List of investigations that contributed in diagnoses of primary amenorrhea

DISCUSSION

Perrault and his colleagues in 1951 published the first report on two sisters with gonadal dysgenesis and with additional sensorineural deafness.[1] Kristiina et al.[2] hypothesized that there is a form of ovarian dysgenesis that is inherited as an autosomal recessive, female-limited disorder. Gottschalk et al.[3] reviewed the neurologic anomalies in previous patients with Perrault syndrome. Neurologic data are available on 14 of 21 girls; 7 of 14 had neurologic abnormalities. They concluded that high incidence of neurologic anomalies suggest that ataxia or mental retardation may not be just coincidental findings, but pleiotropic manifestations of Perrault syndrome. Several reported cases have widened the spectrum of neurologic manifestations in Perrault syndrome. Marlin et al.[4] reported on two sporadic and two familial new cases with sensorineural hearing impairment and ovarian dysgenesis, which are the cardinal signs of Perrault syndrome in females. Only one of them has a nervous system defect. Fiumara et al.[5] reported on two pairs of sisters with gonadal dysgenesis and deafness, cerebral, and ocular involvement who developed a progressive, severe sensory, and motor neuropathy. This observation constitutes further evidence of peripheral nervous system involvement in PS. Based on the clinical observations of known patients; two forms of PS may be distinguished: one apparently non-progressive form and another with apparently progressive axonal-cerebellar degeneration. Nishi et al.[6] reviewed 21 patients from the literature, added ataxic gait, pes equinovarus, nystagmus, limited extraocular movements to the spectrum of neurologic defects in PS. Nikolaou et al.[7] reported on case of sporadic PS in a child with no neurologic involvement. The common pathogenetic relationship between ovarian dysgenesis and sensorineural deafness is unclear. The onset of deafness was noted from 10 months to 31 years. Absence of deafness in a patient with XX female gonadal dysgenesis (XX-GD) does not rule out Perrault syndrome because the patients could develop deafness much later, at an older age.[8] Most patients had moderate to severe sensorineural deafness with mutism among patients with early onset of deafness. The findings of abnormal body proportions noted in our patients have been previously reported by Jacob et al.[9] in their observation of two siblings with Perrault syndrome with Marfanoid habitus.

The pathogenetic basis for the PS is still unclear. No consistent gene mutation has been identified. Pierce et al.[10] studied a small family of mixed European ancestry includes two sisters with well-characterized Perrault syndrome. Whole-exome sequencing of genomic DNA from one of these sisters revealed exactly one gene with two rare functional variants: HSD17B4. Further studies on other families are awaited to confirm the homogeneity of the genetic defect and the underlying molecular defect.

Hormone substitution therapy remains the only therapeutic option. It is aimed at triggering the development of secondary sexual characters and prevents osteoporosis. There remains the unsolved problem of infertility. These issues were discussed with our patient. During the follow up visits, we noticed depression and suicidal tendencies. After a comprehensive psychiatric evaluation, she was diagnosed with major depression and was put on anti-depressant medication.

We did not advice any therapy for mitral valve prolapse as the prognosis in asymptomatic patients with nonsustained arrhythmias and structurally normal hearts is quite good. Thus, the potential deleterious effects of drug therapy probably outweigh any risk from the arrhythmia in this setting. Similarly, no antibiotic prophylaxis or anti-thrombotic prophylaxis was suggested as present guidelines recommends endocarditis prophylaxis for patients only at the highest risk.[1112] She was advised to follow-up for periodic re-evaluation.

CONCLUSIONS

Perrault syndrome is a rare cause of primary amenorrhea or ovarian dysgenesis, but should be considered in a female child with deafness/mutism. Several reported cases have some form of neurologic deficit but our patient did not have any obvious neurological signs or symptoms, but she had marfanoid habitus, an association that was described only once in the literature.[9] The Marfanoid features could be considered as a part of extended phenotype of Perrault syndrome.[13]