Hypogonadotrophic hypogonadism, short stature, cerebellar ataxia, rod-cone retinal dystrophy, and hypersegmented neutrophils: a novel disorder or a new variant of Boucher-Neuhauser syndrome?

Abstract

A number of syndromes have been described in which hypogonadotrophic hypogonadism is associated with multiple somatic and neurological anomalies such as tall stature, anosmia, ataxia, mental retardation, and choroidal dystrophy. [1][2][3][4][5][6][7] The large number of syndromes indicates the considerable clinical heterogeneity associated with hypogonadotrophic hypogonadism. In this report, we describe an unusual constellation of neuroendocrinological findings in an Arab family with three affected sibs. A major finding is hypogonadotrophic hypogonadism associated with short stature owing to gonadotrophic and somatotrophic cellular dysfunction in the anterior pituitary. Although, we discuss several possible modes of inheritance, we speculate that the mode of inheritance of this disorder in this family is autosomal recessive. PATIENTS, MATERIALS, AND METHODSThe family was ascertained through the proband VI.5 (fig 1). All three seemingly affected family members had a detailed evaluation by an endocrinologist, a neurologist, a clinical geneticist, and an ophthalmologist. Three of the four older sibs were examined by the same team and were reported to be normal. The three affected subjects also had electrocardiograms, echocardiograms, brain and pituitary MRI, electromyography, nerve conduction studies, electroretinograms, and electro-oculograms.Patient 1 (VI.5) This male patient is currently 21 years old. He was the product of a 35 week gestation born by normal spontaneous vaginal delivery. At birth, he developed respiratory distress requiring neonatal intensive care for about 6 weeks. He achieved the early milestones of development on time but there is no available record for his growth pattern during the early years.The onset of symptoms was gradual with a slowly progressive ataxic gait around the age of 6 years, which was associated with a progressive decline in his scholastic performance. He presented to us at the age of 20 years, and his height was 1.45 m (<5th centile), weight was 39 kg (<5th centile), and head circumference was 50.5 cm (>2 SD below the mean). He had mild non-progressive bilateral ptosis, and the genital examination showed an infantile penis, small testes, and sparse pubic hair. He had no dysmorphic features or obvious anomalies in the skeletal or cardiovascular systems. He showed evidence of mild impairment of cognitive function (Weschler intelligence scale: verbal IQ 69, performance IQ 47, and full IQ 54). Scanning, dysarthric speech, and multidirectional jerky nystagmus were present. While the saccadic eye movement was abnormal with bilateral hypometric saccades, pursuit eye movement was normal and he had no visual complaints.The neurological evaluation showed normal muscle bulk, without wasting or fasciculations, normal strength throughout, and generalised hypotonia. The deep tendon reflexes were +2 and symmetrical, with a flexor plantar reflex. There were no sensory abnormalities on deep or superficial evaluation. Dysmetria, past pointing, dysdiodochokinesia, and intentional tremors were ...

Boucher–Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature

“…Moderate cognitive impairment (see e.g. cases from [7,18]) and peripheral polyneuropathy may be present in substantial fractions as well. Pes cavus [2,4,19] was described by several authors and movement disorders such as focal (craniocervical) dystonia and chorea may develop in BNS [20].…”

“…Amongst neurological findings dysarthria accompanies cerebellar ataxia in almost all cases and a substantial fraction of BNS patients presents with pyramidal tract findings, underlining the spinocerebellar character of this disease and the often "spastic BNS" presentation [5,7].…”

“…[7,18]). With recent advances in genetic testing in BNS, resulting in the identification of PNPLA6 as the major target gene and an autosomal recessive pattern, this originally clinically defined entity is becoming part of a larger spectrum of neurodegenerative disorders including Gordon Holmes syndrome, hereditary spastic paraparesis, and spastic ataxia [5].…”

“…On the level of single families, a possible autosomal-recessive trait of inheritance (several affected siblings, no genetic testing [2,7,18], has been proposed in the past -often in association with parental consanguinity (e.g. [7,18]).…”

Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome

“…[5][6][7] Here we describe a novel compound heterozygous mutation and a novel homozygous one in the PNPLA6 gene in two Japanese patients with BNS. Furthermore, as hypersegmented neutrophils were reported in two BNS families including our patients, 8,9 we attempted to find hypersegmented neutrophils in BNS genetically proven patients.…”