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Observation |

4H Syndrome With Late-Onset Growth Hormone Deficiency Caused by POLR3A Mutations FREE

Ana Potic, MD; Bernard Brais, MD, MPhil, PhD; Karine Choquet; Raphael Schiffmann, MD, MHSc; Geneviève Bernard, MD, MSc, FRCPC
[+] Author Affiliations

Author Affiliations: Clinic for Child Neurology and Psychiatry, Department of Child Neurology, University of Belgrade, Serbia (Dr Potic); Montreal Neurological Institute (Dr Brais and Ms Choquet) and Montreal Children's Hospital (Dr Bernard), McGill University Health Center, Quebec, Canada; and Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas (Dr Schiffmann).


Arch Neurol. 2012;69(7):920-923. doi:10.1001/archneurol.2011.1963.
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Published online

ABSTRACT

Objective To report a novel clinical and genetic presentation of a patient with 4H syndrome, which is a recently described leukodystrophy syndrome characterized by ataxia, hypomyelination, hypodontia, and hypogonadotropic hypogonadism.

Design Case report.

Setting University teaching hospital.

Patient A 20-year-old male patient with 4H syndrome.

Results The patient was found to have delayed tooth eruption and a late-onset growth hormone deficiency without overt growth failure. He was a compound heterozygote for the novel missense mutations R1005H and A1331T of POLR3A, which codes for the largest subunit of RNA polymerase III.

Conclusion This is the first report of this type of leukodystrophy from southeastern Europe, which suggests that POLR3A mutations should be suspected in patients with hypomyelination and various central nervous system–based endocrine abnormalities.

Figures in this Article

4H syndrome was first described in 2006 as a disorder consisting of hypomyelination, hypogonadotropic hypogonadism, and hypodontia.1 Wolf et al2,3 had previously described 8 patients with ataxia, delayed dentition, and hypomyelination (ADDH), without recognized hypogonadism but with short stature observed in some. An overlap between 4H syndrome and ADDH was assumed (OMIM612440) and supported by sporadic 4H syndrome reports48 describing various nonneurologic symptoms among patients. More recently, tremor-ataxia with central hypomyelination, a childhood-onset hypomyelinating leukodystrophy with prominent tremor and cerebellar signs, has been identified and mapped to chromosome 10q22, along with leukodystrophy with oligodontia (OMIM 607694), in a Syrian family.9,10 The phenotype that we report has the elements of the leukodystrophy syndromes already described above and also a late-onset growth hormone (GH) deficiency as an additional hormonal dysfunction, thus further enlarging the RNA polymerase III (Pol III)–related leukodystrophies spectrum.

METHODS

IDENTIFICATION OF MUTATIONS

Genomic DNA was extracted from peripheral blood lymphocytes using a standard method. Polymerase chain reaction primers were designed using ExonPrimer (http://genome.ucsc.edu) or Primer3 (http://frodo.wi.mit.edu/primer3/) and synthesized by Invitrogen.11 Polymerase chain reactions for the screening of polymerase (RNA) III (DNA directed) polypeptide A, 155-kDa (POLR3A [OMIM 614258]) exons, 5′ and 3′ untranslated regions, and intron-exon boundaries were performed using 40-ng genomic DNA in 10-μL polymerase chain reactions containing 1× polymerase chain reaction buffer, 3nM of magnesium chloride, 10mM of primer mix, and 0.4 U of Taq DNA polymerase (Qiagen). For an amplification reaction, a touchdown program was used. Sequencing analyses were performed at the Genome Quebec Innovation Center, McGill University (Montreal, Quebec, Canada) using an ABI3730 Genetic Analyzer (Applied Biosystems). Sequences were aligned using SeqMan 4.03 (DNAStar) with POLR3A GRCh27/hg19 (http://genome.ucsc.edu) as a reference sequence.

REPORT OF A CASE

A male patient aged 20 years was the second born to nonconsanguineous, healthy parents with no family history of neurological diseases. After an uneventful gestation, birth, and early psychomotor development, the patient first presented at 4 years of age with progressive cerebellar ataxia, bilateral pyramidal deficit, and cognitive decline. Three years later, vertical gaze palsy and loss of pursuit without nystagmus became evident. Focal motor seizures that appeared at 10 years of age were easily controlled with valproate sodium, but replacement with levetiracetam lead to noticeable motor function improvement. Dentition was perturbed and delayed: the first teeth were deciduous mandibular molars erupting at 20 months of age; deciduous incisors were never replaced by permanent teeth.

The results of a neurological examination at 20 years of age showed a normal head circumference, a severe cerebellar syndrome, mild spastic quadriparesis with mild pseudobulbar signs, and preexisting oculomotor abnormalities with normal fundoscopic findings. He was anarthric and confined to a wheelchair, with titubation and poor head control. His full-scale IQ was less than 20, which indicated severe mental retardation according to the Wechsler Intelligence Scale for Children, 3rd edition, confirming a decline from the previous evaluation at 11 years of age (with a full-scale IQ of 42, which indicated moderate mental retardation).

The results of magnetic resonance imaging of the brain performed at 12, 14, and 20 years of age (Figure) showed supratentorial and infratentorial hypomyelination: diffuse white matter hyperintensity on T2-weighted images and an isointense T1-weighted signal (Figure). A mild vermian cerebellar atrophy, moderate cortical atrophy, and thinned corpus callosum were evident at all examinations (data not shown). A small pituitary structure of 5 mm × 5 mm × 5 mm was recorded at 20 years of age (data not shown; with 13 mm × 9 mm × 13 mm being the normal mean structure for the age and sex).12 No other hypophyseal structural anomaly existed. Proton magnetic resonance spectroscopy performed at 12 and 20 years of age revealed a decreased choline to creatine ratio as the only metabolite anomaly within the affected white matter (data not shown). The neuroradiological features have remained substantially unchanged during the 7 years of follow-up.

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Two magnetic resonance imaging scans of the brain of a 20-year-old male patient with 4H syndrome: an axial T1-weighted image (A) and an axial T2-weighted image (B).

The results of routine blood analyses, cerebrospinal fluid testing, and urinalysis were within the normal range. The results of an electroencephalogram showed a slow background activity, and the results of electromyography were normal. Dental radiographs at 18 and 20 years of age confirmed persistent deciduous central incisors with complete tooth buds for all the permanent teeth, excluding hypodontia vera.13

ENDOCRINE EVALUATION

The patient's linear growth has always been unremarkable. At the age of 17 years 9 months, his height was 178 cm, and his weight was 72 kg with a body mass index (calculated as weight in kilograms divided by height in meters squared) of 22.7. However, pubertal development was absent (with a Tanner puberty stage of 0). Hypogonadotropic hypogonadism was confirmed by the low levels of follicle-stimulating hormone, luteinizing hormone, prolactin, and testosterone, along with the absent response to the luteinizing hormone-releasing hormone stimulation test (Table 1). No other hormonal anomaly was revealed at the time. At the age of 20 years, the patient's body mass index and clinical findings were unaltered; genitalia were of prepubertal size and shape, with small-volume testes (1.5 mm3) within the scrotum. His hormonal status remained unchanged except for GH deficiency characterized by undetectable GH during peak basal conditions and a low level of insulin-like growth factor 1 (Table 1). Osteodensitometry revealed advanced osteoporosis resulting from untreated androgen deficiency and loss of ambulation.14

Table Graphic Jump LocationTable 1. Hormonal Status of Patient With 4H Syndrome at Different Ages

RESULTS

The patient was found to be compound heterozygote for c.3014G>A (p.R1005H) in exon 23 and c.3991G>A (p.A1331T) in exon 30. The mutations were found to be present in highly conserved regions and to segregate within the family; both parents were carriers of 1 mutation. Both mutations were absent in more than 350 control chromosomes.

COMMENT

To our knowledge, this is the first report of a patient with 4H syndrome and late-onset GH deficiency. The patient was found to be compound heterozygote for 2 previously unpublished POLR3A mutations. The mutation in exon 23 is located in the same codon as another known 4H mutation (c.3013C>T or p.R1005C).11 Mutations in POLR3A were recently found to cause 3 related leukodystrophies: 4H syndrome, leukodystrophy with oligodontia, and tremor-ataxia with central hypomyelination.11POLR3A encodes for the largest subunit of Pol III, 1 of the 3 polymerases. RNA polymerase III is responsible for the noncoding RNA transcription, including all transfer RNA (tRNA). The hypothesis is that mutations in this gene cause abnormal tRNA transcription leading to cytoplasmic protein synthesis alterations. This mechanism has been suggested for another leukodystrophy: hypomyelinating leukodystrophy type 3, which is caused by mutations in the aminoacyl tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1) gene. The 4H phenotypic spectrum may be explained by the fact that Pol III transcribes genes that are expressed in a cell-type and growth state–dependent manner. These genes play a role in various stresses, such as cellular growth, differentiation, and apoptosis. RNA polymerase III is also thought to be a cytosolic DNA sensor involved in innate immune responses.15

To our knowledge, this is also the first report of such a disorder from southeastern Europe. Only 9 other patients with 4H syndrome have been identified so far.1,48 The overlap between 4H and other leukodystrophies has been observed,3,10,16,17 with the 4H/ADDH overlap being the most prominent one.1,38,10,16,17

Our patient had late-onset GH deficiency in addition to hypogonadotropic hypogonadism and dental anomalies. Among the 8 patients with 4H/ADDH who had short stature,2,47 a partial GH deficiency was found in 1 patient at the age of 14 years, and this finding was associated with small sella turcica.7 Pituitary structure was otherwise reported in only 2 patients with 4H syndrome.5,6 However, all these patients presented with short stature during childhood, necessitating a prompt evaluation. In contrast, the GH deficiency in our patient did not cause the short stature because this deficiency appeared only during the repeated routine hormonal screenings at 20 years of age. Growth hormone stimulation tests (ie, the insulin, glucagon, and arginine tests) are unnecessary for the evaluation of GH deficiency when markedly low levels of insulin-like growth factor 1 and GH are accompanied by other pituitary dysfunctions.18,19 The short stature previously reported in other patients with 4H syndrome indicates that the GH deficiency is likely to be a common feature that should be looked for in this syndrome and in other POLR3A- related disorders. Furthermore, the normal growth rate during childhood and adolescence exhibited by the patient suggests that the insufficiency of sex hormones did not negatively influence GH secretion. The delayed and perturbed dentition without true hypodontia represents another variation of the wide spectrum of dentition anomalies among patients with 4H/ADDH.1,38,16

Unlike the neurological symptoms in some patients with 4H syndrome,5,6,8 our patient's neurological symptoms did progress, and the progression was not associated with the symptoms of fever and infections described in 3 reports on 4H syndrome.2,5,6 Moreover, we observed a clinical progression, even in the context of a lack of change in magnetic resonance imaging findings over time. Although it is unlikely that hormonal status has had an effect on the overall disease course, the untreated androgen deficiency and the new-onset GH deficiency may have contributed to the clinical decline. The clinical improvement of muscle tone and truncal stability after valproate therapy was stopped is noteworthy.

The clinical, electrophysiological, and radiological findings and the extensive laboratory screenings ruled out the diagnosis of other hypomyelinating entities (Table 2).20 Although the hypogonadotropic hypogonadism was key to making the diagnosis, the hypomyelination detected by use of magnetic resonance imaging can be the only abnormality associated with POLR3A mutations.11 The various combinations of neurologic and nonneurologic features should help us to recognize and diagnose Pol III–related leukodystrophy in a timely manner.

Table Graphic Jump LocationTable 2. Known Hypomyelinating Leukodystrophies

ARTICLE INFORMATION

Accepted for Publication: September 8, 2011.

Published Online: March 26, 2012. doi:10.1001 /archneurol.2011.1963

Correspondence: Raphael Schiffmann, MD, MHSc, Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm St, Dallas, TX 75226 (raphael.schiffmann@baylorhealth.edu).

Author Contributions:Study concept and design: Potic, Schiffmann, and Bernard. Acquisition of data: Potic, Choquet, and Bernard. Analysis and interpretation of data: Potic, Brais, Choquet, Schiffmann, and Bernard. Drafting of the manuscript: Potic, Schiffmann, and Bernard. Critical revision of the manuscript for important intellectual content: Potic, Brais, Choquet, Schiffmann, and Bernard. Obtained funding: Potic and Bernard. Administrative, technical, and material support: Potic, Choquet, and Bernard. Study supervision: Potic, Brais, Schiffmann, and Bernard.

Financial Disclosure: Dr Bernard has received fellowship scholarships from Fonds de Recherche en Santé du Québec and Réseau de Médecine Génétique Appliquée.

Funding/Support: This project was financed by La Fondation sur les Leucodystrophies and the European Leukodystrophy Association.

Additional Contributions: We thank the patient and his family for participating in the study.

REFERENCES

Timmons M, Tsokos M, Asab MA,  et al.  Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia.  Neurology. 2006;67(11):2066-2069
PubMed   |  Link to Article
Wolf NI, Harting I, Boltshauser E,  et al.  Leukoencephalopathy with ataxia, hypodontia, and hypomyelination.  Neurology. 2005;64(8):1461-1464
PubMed   |  Link to Article
Wolf NI, Harting I, Innes AM,  et al.  Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy.  Neuropediatrics. 2007;38(2):64-70
PubMed   |  Link to Article
Vázquez-López M, Ruiz-Martín Y, de Castro-Castro P, Garzo-Fernández C, Martín-del Valle F, Márquez-de la Plata L. Central hypomyelination, hypogonadotrophic hypogonadism and hypodontia: a new leukodystrophy [in Spanish].  Rev Neurol. 2008;47(4):204-208
PubMed
Bekiesinska-Figatowska M, Mierzewska H, Kuczynska-Zardzewialy A, Szczepanik E, Obersztyn E. Hypomyelination, hypogonadotropic hypogonadism, hypodontia—first Polish patient.  Brain Dev. 2010;32(7):574-578
PubMed   |  Link to Article
Orcesi S, Tonduti D, Uggetti C, Larizza D, Fazzi E, Balottin U. New case of 4H syndrome and a review of the literature.  Pediatr Neurol. 2010;42(5):359-364
PubMed   |  Link to Article
Outteryck O, Devos D, Jissendi P,  et al.  4H syndrome: a rare cause of leukodystrophy.  J Neurol. 2010;257(10):1759-1761
PubMed   |  Link to Article
Sato I, Onuma A, Goto N,  et al.  A case with central and peripheral hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) plus cataract.  J Neurol Sci. 2011;300(1-2):179-181
PubMed   |  Link to Article
Atrouni S, Darazé A, Tamraz J, Cassia A, Caillaud C, Mégarbané A. Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity?  Am J Med Genet A. 2003;118A(1):76-81
PubMed   |  Link to Article
Chouery E, Delague V, Jalkh N,  et al.  A whole-genome scan in a large family with leukodystrophy and oligodontia reveals linkage to 10q22.  Neurogenetics. 2011;12(1):73-78
PubMed   |  Link to Article
Bernard G, Chouery E, Putorti ML,  et al.  Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy.  Am J Hum Genet. 2011;89(3):415-423
PubMed   |  Link to Article
Ben-Shlomo A, Melmed S. Hypothalamic regulation of anterior pituitary function. In: Melmed S, ed. The Pituitary. 3rd ed. London, England: Elsevier/Academic Press; 2011:21-47
Millett D, Welbury R. Paediatric dentistry. In: Millett D, Welbury R, eds. Ortodontics and Paediatric Dentistry. Edinburgh, Scotland: Churchill Livingstone; 2000:83-105
Devogelaer JP, De Cooman S, Nagant de Deuxchaisnes C. Low bone mass in hypogonadal males: effect of testosterone substitution therapy, a densitometric study.  Maturitas. 1992;15(1):17-23
PubMed   |  Link to Article
Chiu YH, Macmillan JB, Chen ZJ. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway.  Cell. 2009;138(3):576-591
PubMed   |  Link to Article
Wolff A, Koch MJ, Benzinger S,  et al.  Rare dental peculiarities associated with the hypomyelinating leukoencephalopathy 4H syndrome/ADDH.  Pediatr Dent. 2010;32(5):386-392
PubMed
Bernard G, Thiffault I, Tetreault M,  et al.  Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.  Neurogenetics. 2010;11(4):457-464
PubMed   |  Link to Article
Ho KK.2007 GH Deficiency Consensus Workshop Participants.  Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia.  Eur J Endocrinol. 2007;157(6):695-700
PubMed   |  Link to Article
Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ. HyposCCS Advisory Board; U.S. HypoCCS Study Group.  Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?  J Clin Endocrinol Metab. 2002;87(2):477-485
PubMed   |  Link to Article
Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders.  Neurology. 2009;72(8):750-759
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Two magnetic resonance imaging scans of the brain of a 20-year-old male patient with 4H syndrome: an axial T1-weighted image (A) and an axial T2-weighted image (B).

Tables

Table Graphic Jump LocationTable 1. Hormonal Status of Patient With 4H Syndrome at Different Ages
Table Graphic Jump LocationTable 2. Known Hypomyelinating Leukodystrophies

References

Timmons M, Tsokos M, Asab MA,  et al.  Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia.  Neurology. 2006;67(11):2066-2069
PubMed   |  Link to Article
Wolf NI, Harting I, Boltshauser E,  et al.  Leukoencephalopathy with ataxia, hypodontia, and hypomyelination.  Neurology. 2005;64(8):1461-1464
PubMed   |  Link to Article
Wolf NI, Harting I, Innes AM,  et al.  Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy.  Neuropediatrics. 2007;38(2):64-70
PubMed   |  Link to Article
Vázquez-López M, Ruiz-Martín Y, de Castro-Castro P, Garzo-Fernández C, Martín-del Valle F, Márquez-de la Plata L. Central hypomyelination, hypogonadotrophic hypogonadism and hypodontia: a new leukodystrophy [in Spanish].  Rev Neurol. 2008;47(4):204-208
PubMed
Bekiesinska-Figatowska M, Mierzewska H, Kuczynska-Zardzewialy A, Szczepanik E, Obersztyn E. Hypomyelination, hypogonadotropic hypogonadism, hypodontia—first Polish patient.  Brain Dev. 2010;32(7):574-578
PubMed   |  Link to Article
Orcesi S, Tonduti D, Uggetti C, Larizza D, Fazzi E, Balottin U. New case of 4H syndrome and a review of the literature.  Pediatr Neurol. 2010;42(5):359-364
PubMed   |  Link to Article
Outteryck O, Devos D, Jissendi P,  et al.  4H syndrome: a rare cause of leukodystrophy.  J Neurol. 2010;257(10):1759-1761
PubMed   |  Link to Article
Sato I, Onuma A, Goto N,  et al.  A case with central and peripheral hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) plus cataract.  J Neurol Sci. 2011;300(1-2):179-181
PubMed   |  Link to Article
Atrouni S, Darazé A, Tamraz J, Cassia A, Caillaud C, Mégarbané A. Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity?  Am J Med Genet A. 2003;118A(1):76-81
PubMed   |  Link to Article
Chouery E, Delague V, Jalkh N,  et al.  A whole-genome scan in a large family with leukodystrophy and oligodontia reveals linkage to 10q22.  Neurogenetics. 2011;12(1):73-78
PubMed   |  Link to Article
Bernard G, Chouery E, Putorti ML,  et al.  Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy.  Am J Hum Genet. 2011;89(3):415-423
PubMed   |  Link to Article
Ben-Shlomo A, Melmed S. Hypothalamic regulation of anterior pituitary function. In: Melmed S, ed. The Pituitary. 3rd ed. London, England: Elsevier/Academic Press; 2011:21-47
Millett D, Welbury R. Paediatric dentistry. In: Millett D, Welbury R, eds. Ortodontics and Paediatric Dentistry. Edinburgh, Scotland: Churchill Livingstone; 2000:83-105
Devogelaer JP, De Cooman S, Nagant de Deuxchaisnes C. Low bone mass in hypogonadal males: effect of testosterone substitution therapy, a densitometric study.  Maturitas. 1992;15(1):17-23
PubMed   |  Link to Article
Chiu YH, Macmillan JB, Chen ZJ. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway.  Cell. 2009;138(3):576-591
PubMed   |  Link to Article
Wolff A, Koch MJ, Benzinger S,  et al.  Rare dental peculiarities associated with the hypomyelinating leukoencephalopathy 4H syndrome/ADDH.  Pediatr Dent. 2010;32(5):386-392
PubMed
Bernard G, Thiffault I, Tetreault M,  et al.  Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.  Neurogenetics. 2010;11(4):457-464
PubMed   |  Link to Article
Ho KK.2007 GH Deficiency Consensus Workshop Participants.  Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia.  Eur J Endocrinol. 2007;157(6):695-700
PubMed   |  Link to Article
Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ. HyposCCS Advisory Board; U.S. HypoCCS Study Group.  Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?  J Clin Endocrinol Metab. 2002;87(2):477-485
PubMed   |  Link to Article
Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders.  Neurology. 2009;72(8):750-759
PubMed   |  Link to Article

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