Neurosurgical aspects of childhood hypophosphatasia
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- Collmann, H., Mornet, E., Gattenlöhner, S. et al. Childs Nerv Syst (2009) 25: 217. doi:10.1007/s00381-008-0708-3
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Hypophosphatasia (HPP; MIM241510) is a rare inborn error of bone metabolism of recessive inheritance. It is caused by mutations in the gene encoding the tissue-nonspecific alkaline phosphatase. Apart from problems in bone mineralization, growth failure, and premature loss of decidual teeth, the infantile and the childhood types of HPP are associated with premature fusion of cranial sutures.
We report on seven children affected with infantile and childhood HPP who presented with craniosynostosis.
Neurosurgical intervention was necessary in four of them because of intracranial hypertension. In one of these, severe dural calcification posed an unexpected problem during surgery. Secondary ectopia of the cerebellar tonsils were detected in five of the seven patients and caused hydrosyringomyelia in one of them.
Since cranial sutures are frequently involved in infantile and childhood HPP, a multidisciplinary approach for the clinical care is necessary, including long-term neurosurgical surveillance.
KeywordsHypophosphatasiaCraniosynostosisIntracranial hypertensionChiari I malformation
Hypophosphatasia (HPP) is a rare disorder of bone metabolism of autosomal recessive inheritance. It is caused by various defects in the gene coding for the tissue-nonspecific alkaline phosphatase (TNSALP) located on chromosome 1p36. As a consequence, enzymatic activity is diminished to a variable degree resulting in rachitic skeletal changes, short stature, painful lower limbs, gait disturbance, and premature shedding of teeth. Phenotypic expression is highly variable, and the severity of the clinical picture ranges from death in utero or stillbirth to premature loss of permanent teeth and other dental problems in adulthood [16, 18, 20]. As there is a wide overlap of phenotypic features, the commonly used classification into five main clinical subtypes is somewhat arbitrary: First, the congenital or perinatal type presents with severe generalized osteopenia and a nonossified cranial vault. It is associated with stillbirth or death in the first few weeks of life. Second, the infantile type is characterized with severe rachitic skeletal deformities and potential premature fusion of the cranial sutures. Third, the childhood type presents with growth retardation, rachitic osteopathy, and premature loss of decidual teeth. In the adult type, the skeletal changes are mainly confined to short stature and early loss of decidual teeth, as well as problems with permanent dentition. Finally, in the mildest type, named odontohypophosphatasia, the teeth seem to be affected only. Recent studies suggest that mutations at different sites of the TNSALP gene result in different residual enzymatic activity, which may be directly related to the severity and subtype of the phenotype [2, 15, 17].
Although craniosynostosis is a well known feature particularly of the infantile and childhood subtypes [16, 20], few reports have addressed its clinical significance and neurosurgical implications [6, 7, 10, 11, 13, 16, 19]. As in our institution clinical activities focus on both, inflammatory disorders of bone and craniofacial anomalies, we were able to document and study the functional problems resulting from skull involvement in HP. Here, we describe the signs and symptoms, as well as the neurosurgical treatment, in a small but well characterized series of HPP patients.
Patients and methods
Genotypic and phenotypic features of the present series at initial presentation
Age at 1st exam.
Height at first exam.
Serum levels of ALP (U/l)
Age at last exam.
2 cm < P3
1 cm < P3
9 cm < P3
3 cm < P3
Features of cranial pathology
Agea and fused sutures at 1st examination
Affected sutures at follow-up studies
Affected sutures at last examin.
Agea at detection of papilledema
Ectopia of cerebellar tonsils
Agea (mos) at surgery
6 wks: C,L
9 mos: S,C,L
17 yrs: S,C,L
2, 14, 47
1 mo: S
16 yrs: S
16 yrs: S
3 mos: S
18 mos: S,C
11 yrs: S,C, L
78 mos: S,C,L
102 mos: S,C,L
13 mos: S, L
20 mos: S,L
49 mos: SC
78 mos: S,C, L
99 mos: S,C,L
28 mos: C
28 mos: C
28 mos: no
At birth in 1979, this boy presented with a brachycephalic head shape. On radiographs there was evidence of coronal and lambdoid suture synostosis, while a diastatic sagittal suture was noted. A cranial computed tomography (CT) scan was found normal except that the cisterna magna appeared compromized. At the age of 6 weeks, a tense bulging fontanel prompted a morcellation procedure of the anterior skull at another institution. By 9 months of age, the fontanel had closed, bilateral temporal bulging was noted, and multisutural fusion was detected on plain radiographs. Reoperation became necessary at the age of 14 months because of bilateral papilledema. At this time, the premature loss of decidual teeth led to the diagnosis of HPP. Molecular analysis confirmed a heterozygous TNSALP mutation at c.211C>A, corresponding to an amino acid change p.R71S, which was inherited from the father. No additional mutations were found. The subsequent development was normal apart from short stature, mild pain in the lower limbs, and the typical waddling gait. At the age of six, he was referred to our unit with a 1-year history of slowly progressing papilledema. Radiographs showed increased convolutional markings, again suggesting elevated intracranial pressure. A cranial expansion procedure was performed during which intracranial hypertension was confirmed. After surgery, the optic nerve recovered completely. During the following 6 years, a normal intracranial pressure could be estimated from a residual surgical bone defect. At the age of 22 years, routine magnetic resonance (MR) imaging revealed herniation of the cerebellar tonsils down to the C1/C2 level. Hydrosyringomyelia from the midthoracic level up to C4 was noted, which further expanded up to the C2 level within the next 2 years (Fig. 1a, b). As the patient remained asymptomatic, except for mild intermittent numbness of the fingers, he declined surgical intervention. For the following 6 years up to now, he repeatedly reported a stable condition. Because of the early, severe clinical presentation, this patient was classified within an infantile form of HPP, although the fairly benign long-term course of the disease seemed to be more consistent with a childhood type of HPP.
This boy was born in 1990. During the first examination at 26 months of age, a mild scaphocephalic deformity and a slight proptosis of the eyes were noted. Sagittal suture fusion was confirmed on radiographs. Because of the mild degree of skull deformity, surgery was withheld, as there were no signs of elevated intracranial pressure. The optic nerve was ophthalmoscopically examined at 3-month intervals. At the age of 32 months, progressive gait disturbance and the loss of deciduous teeth prompted the diagnosis of childhood-type HPP. Repeated MR imaging at the ages of 4 and 9 years revealed mild nonprogressive herniation of the cerebellar tonsils (Fig. 2). The subsequent course was uneventful; craniosynostosis remained confined to the sagittal suture. No signs of elevated intracranial pressure or optic nerve injury occurred until the last exam at the age of 16. Genetic testing confirmed a compound heterozygous, recessively inherited form of HPP: c.529G>A (p.A177T) was inherited from the mother, while c.203C>T (p.T68M) was transmitted by the father.
In 1995, at the age of 3 months, this boy was referred for treatment of scaphocephaly. Radiographs were consistent with isolated sagittal suture fusion. At the age of 4 months, he was subjected to a standard wide-vertex craniectomy, as described earlier . During operation, the macroscopic aspect of the coronal and lambdoid suture appeared normal. Only after surgery, routine blood testing revealed a decreased level of serum alkaline phosphatase, and the diagnosis of HPP was established. Molecular assessment revealed compound heterozygosity in the TNSALP gene: c.529G>A (p.A177T) originated from the father, c.667C>T (p.R223W) from the mother. The surgically created bone defect reossified within 8 weeks. At the age of 12 months, progressive craniosynostosis affecting the coronal suture was noted on radiographs. The growth of head circumference was retarded. At 22 months of age, ophthalmoscopic routine checks disclosed rapidly progressive papilledema. The patient now presented with recurrent scaphocephalic deformity, mild temporal bulging, and a bony bump at the bregma. Reoperation was performed at the age of 22 months and consisted of a total cranial vault expanding reconstruction. After surgery, the papilledema resolved within 6 weeks. During the 10-year follow-up, the patient remained symptom-free with regard to his mental development and head growth. However, he suffered from severe gait problems, leg pain, and a mild thoracic dysplasia. At the age of 13 years, MR imaging revealed normal intracranial findings. The boy’s phenotype of HPP shows overlapping features of infantile and childhood HPP. Based on a 10-year follow-up, we consider him as an early manifestation of the childhood form.
This girl, born in 1997, had symptoms suggestive of HPP since early infancy, but the diagnosis was not established until the age of four. At the age of 6.6 years, she was referred because of recurrent headaches and vomiting. She presented with an oxycephalic head shape including a marked bony bump at the bregma. Ophthalmoscopic findings had always been normal, but on radiographs, pansynostosis and increased convolutional markings were noted. MR imaging revealed distinct tonsillar herniation without concurrent syrinx, and mild enlargement of the ventricles (Fig. 3). Surprisingly, epidural pressure monitoring showed normal values. The girl’s complaints resolved spontaneously, and surgery was declined by the parents. Yearly follow-up checks and routine ophthalmoscopy at 3-month intervals revealed normal findings during the next 4 years. By genetic testing, a compound heterozygous mutation of the TNSALP gene was detected: c.571G>A (p.E191K) originating from the father and c.1001G>A (p.G334D) transmitted by the mother.
The brother of the aforementioned patient was born 2002. He was, thus, diagnosed with HPP at 4 months of age and, therefore, kept under close surveillance. He subsequently developed mild features of HPP: Mild signs of rickets, mild thoracic dysplasia, and frontal bossing. At 13 months, radiographs demonstrated a fused sagittal suture and an impending fusion of the lambdoid suture although the still open fontanel was not bulging. Between 15 and 19 months, he developed bilateral papilledema. MR imaging revealed mild ectopia of the left cerebellar tonsil. He underwent a surgical cranial vault expansion during which synostosis of the sagittal and lambdoid sutures was confirmed. Postoperatively, the optic nerve pathology normalized within a few weeks. Since then, he has remained symptom-free up to his present age of 6.1 years. This patient carried the same mutations as his sister. Both siblings were diagnosed with a childhood type of HPP based on clinical and biochemical findings.
This girl, born 1999, was referred at the age of 4.1 years with a de novo diagnosis of HPP of the childhood type. She was of short stature, complained of pain in the legs, and showed the typical waddling gait. Her head shape was oxycephalic with a bregmatic bump and a midsagittal bony ridge. Examination disclosed severe chronic papilledema, fusion of sagittal and coronal suture, and increased convolutional markings (Fig. 4a). On MR images, the cerebellar tonsils protruded just below the level of the foramen magnum. A cranial expansion procedure was planned for the patient. However, during surgery, the dura was found calcified and firmly adhering to the inner surface of the vault. On the radiographs, this calcification was suspected only retrospectively (Fig. 4a). It had not been anticipated on preoperative CT scans (Fig. 4b). Elevation of the scheduled bone flaps caused several dural defects, which had to be covered with periosteal grafts (Fig. 4c). The cerebral cortex remained intact. Surgery was completed as a morcellation procedure, i.e., the bone flaps were loosely replaced on the dural surface. Histological analysis of some bone specimen revealed extensive calcinosis and metastatic ossification of the dura (Fig. 5a–c). In terms of function, the operation was successful: the intracranial pressure normalized and the papilledema resolved leaving the optic nerve function intact. The girl remained well during the follow-up of 5 years. Also, a gradual closure of the operative bone defects was noticed. On repeated MR images at 8.8 years of age, the intracranial pathology remained unchanged. There was no hydrosyringomyelia, but a mild scoliosis had developed. Genetic analysis revealed a compound heterozygosity for the mutations c.212G>A (p.R71H) from paternal origin and c.571G>A (p. E191K) from maternal origin.
A review of the literature reveals only scanty case reports of premature sutural fusion in HPP. Data about its true incidence is lacking. Yet, craniosynostosis is considered a known feature in the infantile and childhood types of HPP [16, 20], while it is missed in the adult and odonto-HPP types, thereby suggesting a direct relationship with the degree of enzymatic deficiency. However, biochemical analysis in our cases did not reveal any overt differences from the 13 other childhood HPP individuals not affected by craniosynostosis. No particular genetic mutational pattern was found in the synostotic individuals. In addition, the age range and the distribution of subtypes did not differ between these two subgroups.
Skull pathology in HPP has been reported as hypomineralization, which, in the most severe perinatal form, results in a “caput membranaceum”. In the less severe infantile form, widely diastatic sutures or at least multiple Wormian bones have been reported [10, 13]. They seem to precede sutural obliteration and should, therefore, be considered as functionally closed sutures. In fact, MacPherson and colleagues found uncalcified osteoid as substrate mimicking this sutural gap . According to the present data, premature fusion in HPP appears to start with the sagittal or coronal suture. However, synostosis may progressively involve all main cranial sutures during childhood. In these cases, intracranial hypertension putting the optic nerve at risk should be anticipated. Of importance, the lambdoid suture tends to close early, thereby possibly preventing normal expansion of the posterior fossa. This may explain the herniation of the cerebellar tonsils as a secondary phenomenon. A similar condition has been described in the Crouzon syndrome  and in the combined isolated sagittal and lambdoid suture synostosis . However, radiological evidence of an open lambdoid suture as in cases 3 and 6 does not preclude tonsillar herniation. Ectopic cerebellar tonsils in craniosynostosis have been shown to be related to hydrostatic hydrocephalus and to hydrosyringomyelia . In our series, no patient presented with shunt-dependent hydrocephalus, but hydrosyringomyelia was detected in one of them at adolescence. Taking the unpredictable evolution of hydrosyringomyelia into account, it seems advisable to keep all patients with ectopic cerebellar tonsils under long-term surveillance.
As with other types of progressive multisutural craniosynostosis, surgical treatment should result in a substantial increment of intracranial volume. In infancy, this goal may be achieved by simple linear craniectomy or a morcellation procedure, but in childhood, we consider some kind of active cranial vault expansion to be more appropriate . Extensive dural ossification in HPP as in patient 6 may pose a significant surgical problem. To our knowledge, this condition has not been described hitherto. Its causative mechanism remains to be elucidated. Of note, none of our patients developed epileptic seizures, which have been reported as a feature of infantile type of HPP . Seizures seem to be related to cerebral intracellular pyridoxal-5-phosphate deficiency, as they respond well to pyridoxine administration .
In conclusion, our data suggest that craniosynostosis is a common feature in HPP of the infantile and childhood types. It often progressively involves all cranial sutures and poses significant functional risks to the optic nerves, as well as the spinal cord. As other signs of HPP may not be obvious at first examination, the serum levels of alkaline phosphatase should be determined in any case of putative isolated craniosynostosis. Conversely, the evaluation of HPP in childhood should include plain radiographs and, in case of premature sutural fusion, MR imaging and repeated ophthalmoscopic assessment. With regard to the progressive nature of craniosynostosis, careful surveillance is recommended throughout childhood until adolescence and, in the presence of Chiari I malformation or hydrosyringomyelia, probably throughout life.