American Journal of Medical Genetics 134A:215 –219 (2005) Clinical Report Cerebellar Hypoplasia—Endosteal Sclerosis: A Long Term Follow-Up Heval M. Ozgen,1 Wouterina C.G. Overweg-Plandsoen,2 Janneke Blees-Pelk,3 Philip P. Besselaar,4 and Raoul C.M. Hennekam1,5* 1 Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands 3 Department of Rehabilitation, Rehabilitation Center ‘De Trappenberg,’ Huizen, The Netherlands 4 Department of Pediatric Orthopedic Surgery, Academic Medical Center, Amsterdam, The Netherlands 5 Department of Clinicial Genetics, Academic Medical Center, Amsterdam, The Netherlands 2 Cerebellar hypoplasia with endosteal sclerosis is an infrequent entity that has been described in only four cases. Major clinical symptoms are cerebellar hypoplasia causing ataxia, hypotonia, mild to moderate developmental delay, microcephaly, growth retardation, endosteal sclerosis, tooth eruption disturbances, and hip dislocations. We report on a girl with this entity, whom we followed for 11 years. The endosteal sclerosis remained stationary over time, as were the clinical neurological symptoms, but neuroadiological symptoms were slowly progressive. We provide a short review of this probably autosomal recessively inherited disorder. ß 2005 Wiley-Liss, Inc. KEY WORDS: endosteal sclerosis; osteosclerosis; cerebellar hypoplasia; ataxia; mental retardation INTRODUCTION In 1986 Claude Stoll reported a girl with cerebellar hypoplasia and endosteal sclerosis. Clinical symptoms were ataxia, tremor, nystagmus, optic atrophy, hearing loss, and mental retardation. He suggested this to be a hitherto undescribed entity [Stoll et al., 1986]. In 1991, Charrow et al. [1991] reported three patients with a similar phenotype. Here we present the long term follow up in another patient with the same diagnosis to determine the natural course of the disorder. CLINICAL REPORT The proband, the second child of healthy, non-consanguineous parents, was born at term after an uneventful pregnancy and delivery. Weight at birth was 3,950 g (90th–97th centile), length and skull circumference were not recorded. Mild pedes equinovari were noted at birth which did not need *Correspondence to: Raoul C.M. Hennekam, Department of Pediatrics, Floor G8 Room 239, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. E-mail: r.c.hennekam@amc.uva.nl Received 16 July 2004; Accepted 13 December 2004 DOI 10.1002/ajmg.a.30589 ß 2005 Wiley-Liss, Inc. therapy. At 1 year bilateral hip dysplasia and coxa valga were detected, needing bracing. First motor milestones were reached at a slightly delayed age: sitting at 13 months, walking with help at 19 months. At 2 years she was referred because of a gait disturbance. At that same age it was noted that her speech development was slow and possibly dysarthric. On examination her height was 80.0 cm (3rd centile), weight was 10.9 kg (3rd centile), and OFC was 48.5 cm (50th– 75th centile). Her facial features showed a long philtrum and an unusual eruption pattern of the primary teeth with lack of eruption of the four lateral incisors. Neurologically, she had dysarthria, and no abnormalities of the cranial nerves, especially no nystagmus was noticed. There was hypotonia of all extremities, brisk jerks, no Babinski sign, a cerebellar ataxic gait and slight dysmetria of both arms with normal fine motor performance. Ophthalmological examination showed myopia and leftsided pale papil but gave otherwise normal results. Especially no firm proof of nystagmus was found. The electromyography, brainstem evoked potentials, and visual evoked potentials all gave normal results. The MRI of the brain at 29 months showed severely delayed myelination (myelination was according to 4–6 months), focal white matter abnormalities adjacent to the ventricles in the parieto-occipital region, and generalized cerebellar atrophy of both vermis and hemispheres (Fig. 1a). A complete metabolic screen including blood cell counts, electrolytes including Cu, serum alkaline phosphatase, protein electrophoresis, cholesterol, triglycerid and HDL/LDL levels, CPK, carnitine levels, vitamin E levels, general urinary screen, a screen for a peroxisomal disturbance through long chain fatty acid levels, a screen for mitochondrial disorders through plasma and urinary lactate and pyruvate levels, and lysosomal enzymes were all within normal limits. Spinal fluid levels of glycose, lactate, and protein were normal, as was a cell count. Chromosomal studies gave a normal female karyotype (46,XX). No firm diagnosis was made at that time. In the ensuing 2 years the girl continued to have walking difficulties, which was mainly caused by the ataxia and not the hip dysplasia, but to prevent deterioration a bilateral intertrochanteric varus osteotomy combined with a unilateral Salter innominate osteotomy was performed at the age of 4.5 years. During surgery the proximal femoral metaphysis was found to be sclerotic; healing and functional recovery was uneventful. Pathological exams showed subcortical sclerosis which could not be further classified. A skeletal survey revealed a generalized sclerosis with narrowing of the medullary space of the long bones, which was most expressed in the pelvis and femora. Ossification of hands, feet, and skull was normal. In retrospect earlier X-rays did already show this endosteosclerosis (Fig. 2a). 216 Ozgen et al. Fig. 1. Neuroradiological studies in the proband at the age of 29 months (a–c) and 6 years (d). a: Sagittal section; (b) axial section, T1w; (c, d): Axial sections, T2w. Note increase in cerebellar hypoplasia with time, and stationary delay in myelination and in focal white matter abnormalities. Cerebellar Hypoplasia—Endosteal Sclerosis 217 Fig. 2. Radiographic studies of the pelvis at 12 months (a) and 11 years (b). Note the generalized sclerosis of pelvis and femora, that remains unchanged. At 12 months there is unilateral subluxation of the hip, at 10 years there is mild irregularity of the anterior outer rim on the right side of the iliac bone due to the Salter osteotomy at age 4.5 year. The X-ray of the hand at age 11 years (c) shows minimal increased bone density in the carpus and radius/ulna, also visible in unusual dense epiphyses of the medial phalanges. Neurologically, she was examined at regular intervals. At 4 years she showed Babinski signs, and a nystagmus was detected. The ataxia, dysarthria, intention tremor and normal facial mimicry remained unchanged. Her OFC followed the 50th centile. At 6 years ophthalmological exam still showed a somewhat pale left papil. Repeated MRI brain at that age showed no progress in myelination and more pronoumced cerebellar atrophy with enlarged fissures compared to the folia. 218 Ozgen et al. The focal white matter abnormalities had remained unchanged (Fig. 1d). Her cognitive development was slow. When tested (WIPPSI) at 7 years she had a cognitive IQ level of 64. At 11 years she still needed a walking aid and was not able to walk without support due to the cerebellar ataxic gait. She had a short concentration span and dysarthric speech. There was an overt nystagmus. She showed dysmetria of both arms. The knee and ankle jerks were very brisk and she had bilateral Babinski signs. A follow-up skeletal survey showed the generalized sclerosis of the pelvis and femora to be unchanged (Fig. 2b). The sclerosis did also involve the humeri, ribs, and lower vertebra but less severely. In the hands and (to a lesser extend) the feet some of the medial phalangeal epiphyses were ivory, but otherwise the acral ossification was normal (Fig. 2c). The proximal and medial phalanges of the hands showed mild undertubulation, and the femoral epiphyses were irregularly formed, but otherwise no skeletal abnormalities were found. DISCUSSION The symptoms in all four earlier reported patients with cerebellar hypoplasia—endosteal sclerosis are compared to those in the present patient in Table I. The reported patients share as characteristics the congenital cerebellar hypoplasia, hypotonia, ataxia, mental retardation, endosteal sclerosis, short stature, hip dislocations, and tooth eruption disturbances. Other, less common manifestations are microcephaly, strabismus, nystagmus, optic atrophy, and dysarthria. We have contacted the authors of the earlier reports to learn of any further developments in the original patients, but unfortunately all were lost to follow-up [Stoll, 1997 (personal communication); Charrow, 1997 (personal communication)]. Cerebellar hypoplasia denotes reduced cerebellar volume, the cerebellar shape being in principle normal. Cerebellar hypoplasia is etiologically a very heterogenous condition. The number of entities that show cerebellar hypoplasia as a symptom is large. Major groups of causes are central nerval system malformations, metabolic disturbances, viral infections, chromosome aberrations, teratogenic agents, and isolated, genetically determined hypoplasias [Boltshauser, 2004]. Clinically the present patient does not show a progression in symptoms, but neuroradiologically there is a slow but steady progression in symptoms. It is well known that slowly progressive ataxia can be difficult to differentiate from non- progressive ataxia [Steinlin et al., 1998]. A mild to moderate developmental delay is common in children with ataxia [Steinlin et al., 1998], as are seizures, which the present patient never experienced. Endosteal sclerosis is one of the group of entities characterized by increased radiodensity of bones. Increased radiodensity may be caused by an increased bone mass (hyperostosis) or increased mineral content (osteosclerosis) [Hall, 2002]. Osteosclerosis can be seen in isolated, skeletal abnormalities such as the different forms of osteopetrosis or entities combining skull sclerosis with limb sclerosis, in lethal entities as Raine syndrome (OMIM 259775), or in entities that combine osteosclerosis with other symptoms such as renal tubular acidosis (OMIM 259730), enamel hypoplasia in dysosteosclerosis (OMIM 224300), enamel hypoplasia together with facial characteristics and acroosteolysis in pycnodysostosis (OMIM 265800), enamel hypoplasia with facial characteristics, cutaneous syndactylies, and mental retardation in Lenz–Majewski syndrome (OMIM 151050), enamel hypoplasia, characteristic face, cutaneous syndactylies, and microcornea in oculodentodigital syndrome (OMIM 164200), cleft palate and cranial nerve deficits in osteopathia striata with cranial sclerosis (OMIM 166500), and contractures and vascular and lymphatic malformations in melorheostosis (OMIM 155950) [Gorlin et al., 2001]. In none of these entities the osteosclerosis goes along with cerebellar hypoplasia and the ensuing neurological symptoms, which should allow differentiation. The endosteal sclerosis in the present patient has remained more or less stationary over time, sparing the skull, and only mildly present in the thorax and distal acra. The patient reported by Stoll and co-workers [1986] had been born to consanguineous parents; all other couples did not show consanguinity. Charrow et al. [1991] reported a brother and sister that were affected with equal severity, the other reported patients were the only affected patients in their families. No chromosome abnormality has been reported. At present it seems most likely that endosteal sclerosis—cerebellar hypoplasia follows an autosomal recessive inheritance, although the number of reported cases is too small to exclude other patterns of inheritance. In conclusion, the patient presented here further confirms the existence of cerebellar hypoplasia—endosteal sclerosis as a separate entity. During 11 years of follow-up the neurological symptoms remained stable but neuroradiologic studies showed a slow progression. Her developmental delay TABLE I. A Comparison of the Findings in the Present Patient Compared to Those From Literature Authors Gender Age at description (years) Developmental delay Height (in centiles) Microcephaly Cerebellar hypoplasia Ataxia Hypotonia Strabismus Nystagmus Optic atrophy Hearing loss Long philtrum Abnormal teeth eruption Endosteal sclerosis Congenital hip dislocation Stoll et al. [1986] M 20 months þ
P5 þ þ þ þ þ þ þ þ þ þ þ þ Charrow et al. [1991] M 22 months þ P5–10 þ þ þ þ  þ  þ/  ? þ þ F 6 10/12 þ
P5 þ þ þ þ  þ  ?  þ þ þ M 8 8/12 þ
P5  þ þ þ þ ? ? ? þ þ þ þ Present patient All F 11 þ P3  þ þ þ þ þ þ  þ þ þ þ 3M/2F 5/5 4/5 < P5 3/5 5/5 5/5 5/5 3/5 4/4 2/4 1/3 3/5 4/4 5/5 5/5 Cerebellar Hypoplasia—Endosteal Sclerosis became more clear with time. The endosteal sclerosis remained unchanged. ACKNOWLEDGMENTS We thank the family for their kind co-operation. REFERENCES Boltshauser E. 2004. Cerebellum-small brain but large confusion: A review of selected cerebellar malformations and disruptions. Am J Med Genet 126A:376–385. 219 Charrow J, Poznanski AK, Unger FM, Robinow M. 1991. Autosomal recessive cerebellar hypoplasia and endosteal sclerosis: A newly recognized syndrome. Am J Med Genet 41:464–468. Gorlin RJ, Cohen MM, Hennekam RCM. 2001. Syndromes of the head and neck, 4th edn. New York: Oxford University Press. pp 281–304. Hall CM. 2002. International nosology and classification of constitutional disorders of bone. Am J Med Genet 113:65–77. Steinlin M, Zangger B, Boltshauser E. 1998. Non-progressive congenital ataxia with or without cerebellar hypoplasia: A review of 34 subjects. Develop Med Child Neurol 40:148–154. Stoll C, Talon P, Alembik Y, Levy JM. 1986. Hypoplasie cerebelleuse congenitale avec lesions osseuses. Ann Pediatr (Paris) 33:417–421.