Boucher Neuhäuser syndrome (BNS) is a rare disorder defined by the clinical triad of hypogonadotropic hypogonadism, spinocerebellar ataxia, and chorioretinal dystrophy. 1 We are presenting this rare syndrome in twins, which has not been described to the best of our knowledge.
The proband is a 25‐year‐old female product of a nonconsanguineous marriage born after a twin pregnancy with normal birth and developmental history. At 17 years of age, she was evaluated for amenorrhea. Examination revealed normal external genitalia and secondary sexual characteristics. However, an ultrasound of the abdomen and pelvis revealed a hypoplastic uterus with small ovaries. The hormonal profile was suggestive of hypogonadotropic hypogonadism. At 16 years of age, she complained of gradually progressive visual disturbances (visual acuity, 6/24 oculus dexter (OD) and 6/36 oculus sinister (OS)). Fundoscopy and intraocular pressure were normal. At 18 years of age, she noticed tremors in her hands bilaterally while threading a needle with imbalance while walking. Breast development was normal (Tanner stage 4) with the presence of pubic hairs. She scored 28/30 in the Mini‐Mental State Examination (MMSE). Extraocular eye movements were complete with the presence of macro square wave jerks and end‐gaze nystagmus. She had cerebellar signs with an impaired finger–nose test, dysdiadochokinesia, impaired heel‐knee‐shin test, and impaired tandem gait (Video 1). Her motor and sensory examination was normal. Deep tendon reflexes were 2+ with flexor plantar response.
Video 1.
Demonstration of appendicular and gait ataxia and eye movement abnormalities in the form of gaze‐evoked nystagmus and broken pursuits in the proband.
The proband's younger twin sister also had a similar chronology of amenorrhea (hypoplastic uterus with hypogonadotropic hypogonadism) followed by visual disturbances and cerebellar ataxia. A detailed ophthalmological evaluation showed the best corrected visual acuity of 6/12 bilaterally. The fundus showed mild pigmentary retinal deposition (Fig. 1). The cerebellar signs were more marked than her sister's (Video 2). She scored 27/30 on the MMSE, with mild impairment in recent memory, sustained attention and calculation.
FIG. 1.
(A) Right eye. True color fundus picture of the right eye shows a hypoplastic disc with pseudo‐disc edema. The inferonasal quadrant has a neuro‐retinal rim and chorioretinal thinning (yellowish‐orange choroidal vessels are seen). The vessels show a situs invertus pattern (vessels are emerging from the nasal aspect of the disc). (B) Left eye. A true color fundus picture of the left eye shows a hypoplastic disc with pseudo‐disc edema. There is a neuro‐retinal rim and chorioretinal thinning in the inferonasal quadrant. The major retinal veins showed mild tortuosity, although there was no dilation.
Video 2.
Demonstration of cerebellar signs with postural tremors and gaze‐evoked nystagmus in her twin sister.
Brain magnetic resonance imaging (MRI) in both patients revealed severe cerebellar atrophy (Fig. 2). Clinical exome sequencing revealed compound heterozygous variants in the patatin‐like phospholipase domain‐containing 6 (PNPLA6) gene (nonsense variation in the exon 28 [c.3248G>A] that resulted in a stop codon and premature truncation of the protein at codon 1083 [p.Trp1083Ter] and missense variation in exon 34 [c.4082G>A] that resulted in the amino acid substitution of glutamine for arginine at codon 1361 [p.Arg1361Gln]) in both twins. The variant occurred in the patatin‐like phospholipase domain of the PNPLA6 protein. This variant has not been reported in the 1000 genomes and was found to be damaging by in silico prediction tools (MutationTaster2 (Build NCBI 37/Ensembl 69)).
FIG. 2.
Brain magnetic resonance imaging axial T2‐weighted and sagittal images showing cerebellar atrophy: (A,B) case 1 and (C,D) case 2.
BNS is a rare autosomal recessive disorder caused by a mutation in the PNPLA6 gene. The PNPLA6 gene can present with a broad spectrum of neurodegenerative diseases by virtue of its role in lipid metabolism, intracellular membrane trafficking, and axonal maintenance. 2 It has a heterogeneous presentation with an age range from 1 to 40 years. Cerebellar ataxia is the presenting manifestation in about 36% of patients, with one third presenting with visual loss and about one fourth with delayed puberty. 3 Several additional presentations have been described, ranging from spastic paraparesis, cognitive impairment, and motor neuropathy to movement disorders (chorea and dystonia). 4 Mutations in the PNPLA6 gene have been described in SPG 39 (spastic paraplegia), Gordon Holmes syndrome, Laurence‐Moon and Oliver‐McFarlane syndrome apart from BNS, expanding the spectrum with a varied combination of spasticity, ataxia, distal muscle wasting, hypogonadism, chorioretinal dystrophy, dwarfism, alopecia, and trichomegaly. Ataxia with hypogonadism phenotype can also be seen in RNF216/OTUD4 mutations, causing defects in ubiquitination, and STUB1/CHIP mutations involved in cellular protein homeostasis. Ataxia with hypogonadism has also been reported in the mitochondrial MT‐ATP6 mutation as well. Among the MRI changes in BNS, diffuse cerebellar atrophy is the most consistent finding with selective atrophy of the superior and dorsal part of the vermis, which was present in our patient as well. 5
Author Roles
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
S. Mahajan: 1B, 1C, 2A, 2B
S. Mehta: 1A, 1B, 1C, 2A, 2B
J.S.: 1B, 1C
B.T.: 1B, 1C
N.B.: 1B, 1C
V.L.: 1C, 2B
Disclosures
Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. However, informed consent was obtained and is submitted with the manuscript.
Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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