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Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 50-53

Fractures, abnormal skull shape, and metabolic acidosis in a young child

Department of Pediatrics, Pediatric Nephrology Center of Excellence, Pediatric Nephrology Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

Date of Web Publication17-May-2019

Correspondence Address:
Sherif Mohamed El-Desoky
Department of Pediatrics, Pediatric Nephrology Center of Excellence, Pediatric Nephrology Unit, Faculty of Medicine, King Abdulaziz University, P. O. Box: 80215, Jeddah 21589
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_7_19

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How to cite this article:
El-Desoky SM, Kari JA. Fractures, abnormal skull shape, and metabolic acidosis in a young child. Asian J Pediatr Nephrol 2019;2:50-3

How to cite this URL:
El-Desoky SM, Kari JA. Fractures, abnormal skull shape, and metabolic acidosis in a young child. Asian J Pediatr Nephrol [serial online] 2019 [cited 2021 Jul 25];2:50-3. Available from: https://www.ajpn-online.org/text.asp?2019/2/1/50/258564

  Case History Top

A 3-year-old boy was admitted to the pediatric intensive care unit with progressive shortness of breath, requiring therapy with oxygen for 3 weeks, followed by worsening respiratory distress for 2 days. The child was born at full term to nonconsanguineous parents and weighed 2 kg at birth. He had recurrent chest infections and multiple skeletal fractures with minor trauma since early infancy, which was interpreted elsewhere as osteogenesis imperfecta. He had also been operated for cataract in the right eye and had poor vision, developmental delay with regression, and failure to thrive. The two younger siblings were asymptomatic.

At presentation, the child had respiratory distress with desaturation on room air. He weighed 4.4 kg and was 65 cm long; with weight and height at -7.4 and -8.3 standard deviation scores, respectively. The skull was tower-shaped. Both eyes had proptosis and horizontal, symmetrical and conjugate nystagmus. The vision was severely impaired such that he could not fix or follow objects. The right pupil was sluggishly reactive to light while the left eye had no reaction. The left eye had high intraocular pressure, between 26 and 35 mm Hg. The child was severely hypotonic. [Table 1] lists results of blood and urine investigations at presentation.
Table 1: Investigations at presentation and follow-up

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Initial blood gas showed pH 7.24, PCO2 56 mm Hg, bicarbonate 14 mmol/l, anion gap 16, and base deficit of -10 mmol/l, suggesting combined metabolic and respiratory acidosis. Persistent respiratory failure necessitated mechanical ventilation followed by continuous positive airway pressure during hospital stay. [Table 1] lists the results of investigations during hospital stay. [Figure 1] show the skeletal survey radiographs and imaging of the brain. Abdominal ultrasound and echocardiography did not reveal significant abnormalities. Due to repeated packed red cells transfusions for severe anemia, blood sampling for genetic testing was not done. The child succumbed to septicemia 5 weeks after admission.
Figure 1: Imaging findings. Panels indicate the radiographs of the (a) chest and upper limbs; (b) lower limbs; and (c) skull, and imaging of the brain by (d and e) computed tomography and (f) magnetic resonance imaginga

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  Questions Top

  1. What are the chief findings in skeletal radiographs?
  2. What are the findings on computed tomography and magnetic resonance imaging of the brain [Figure 1]?
  3. What is the interpretation of blood and urine chemistry [Table 1]?
  4. What is the likely diagnosis?
  5. What are the principles of management?

  Answers Top

  1. Both upper limbs radiographs show multiple old and new fractures. Bowing of the lower limb long bones, osteopenia, and splaying and cupping of the metaphysis suggest rickets. The skull has a “copper-beaten” appearance
  2. Computed tomography of the brain shows abnormal skull shape, with towering in the frontal region (oxycephaly) and compound craniosynostosis (sagittal and coronal sutures). Magnetic resonance imaging shows bilateral abnormal white-matter signal intensities, with hyperintensities in bilateral occipital and posterior parietal regions and adjacent to both occipital horns of the lateral ventricles
  3. Investigations indicate normal anion gap metabolic acidosis and severe hypophosphatemia with phosphaturia (suggested by low tubular reabsorption of phosphate and maximum rate of tubular phosphate reabsorption to the glomerular filtration rate) and glucosuria. There was no bicarbonate wasting (fractional excretion of bicarbonate), likely because serum bicarbonate at evaluation was low. Reports suggest Fanconi syndrome with proximal renal tubular acidosis
  4. Proximal renal tubular acidosis with Fanconi syndrome, severe hypophosphatemic rickets, and ocular abnormalities suggest the diagnosis of oculocerebrorenal syndrome of Lowe (OCRL). Craniosynostosis appears to be secondary to severe rickets
  5. Management includes oral phosphate supplements for hypophosphatemia, correction of metabolic acidosis and hypokalemia with potassium citrate, and cranial vault remodeling, if indicated, for craniosynostosis.

  Discussion Top

We present a case of proximal renal tubular acidosis associated with severe hypophosphatemic rickets and craniosynostosis, neurodevelopment regression, and eye anomalies, leading to a clinical diagnosis of Lowe syndrome.[1]

Craniosynostosis, referring to premature fusion of cranial sutures, is uncommon with an incidence of 1 in 1750–2100 live births.[2] Thompson and Hayward classify primary craniosynostosis as single-sutural or isolated synostoses, complex (multiple) craniosynostosis, and syndromic craniosynostosis. Secondary craniosynostosis may occur in association with hypophosphatemic rickets, hyperthyroidism, mucopolysaccharidosis (Hurler and Morquio syndromes), and in hematological conditions such as polycythemia vera or thalassemia.[3],[4],[5] Craniosynostosis in X-linked hypophosphatemic rickets was first described by a Norwegian pediatrician in 1951,[6] but is also known to follow nutritional rickets.[7] One-third of 59 children with either active rickets or past therapy for rickets showed craniosynostosis, of whom three required decompressive craniectomies.[8] Overall, hypophosphatemic rickets are the most common metabolic cause of secondary craniosynostosis.[9] These patients require monitoring for signs of raised intracranial pressure and might need evaluation for cranial vault remodeling.[9]

In 1952, Lowe et al. described a unique syndrome with organic aciduria, decreased renal ammoniagenesis, hydrophthalmia, and mental retardation.[1] In 1954, a renal Fanconi syndrome was recognized as being associated with the condition, termed Lowe syndrome.[10] The condition was later understood to be secondary to mutations in OCRL, also responsible for Dent-2 disease. Both are rare X-linked renal tubulopathies that usually progress to chronic kidney failure.[11] Magnetic resonance imaging of the brain may show one of the two patterns of the lesions: hyperintensities on T2-weighted images and periventricular cystic lesions.[12] Most (94%) female carriers of Lowe syndrome show punctuate white-to-gray lenticular opacities on slit-lamp examination that involve all layers of cortex and are distributed radially.[13]

The quality of life for patients with Lowe syndrome depends on the severity of renal and neurological manifestations. Patients rarely survive beyond 40 years of age and usually succumb to kidney disease, hypotonia, infections, or seizures.[14] In a patient with Lowe syndrome in whom an intronic mutation leading to pseudoexon inclusion in the mRNA causes OCRL-1 protein loss, an exon skipping strategy was shown to successfully restore significant levels of OCRL mRNA and protein, suggesting there is hope on the horizon.[15]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Lowe CU, Terrey M, MacLachlan EA. Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation; a clinical entity. AMA Am J Dis Child 1952;83:164-84.  Back to cited text no. 1
Renier D, Le Merrer M, Arnaud E, Marchac D. Etiology of craniosynostosis. Neurochirurgie 2006;52:228-37.  Back to cited text no. 2
Thompson D, Jones B, Hayward R, Harkness W. Assessment and treatment of craniosynostosis. Br J Hosp Med 1994;52:17-24.  Back to cited text no. 3
Mathijssen IM. Guideline for care of patients with the diagnoses of craniosynostosis: Working group on craniosynostosis. J Craniofac Surg 2015;26:1735-807.  Back to cited text no. 4
Ursitti F, Fadda T, Papetti L, Pagnoni M, Nicita F, Iannetti G, et al. Evaluation and management of nonsyndromic craniosynostosis. Acta Paediatr 2011;100:1185-94.  Back to cited text no. 5
Imerslund O. Craniostenosis and Vitamin D resistant rickets. Acta Paediatr 1951;40:449-56.  Back to cited text no. 6
Wang PI, Marcus JR, Fuchs HE, Mukundan S Jr. Craniosynostosis secondary to rickets: Manifestations on computed tomography. Radiol Case Rep 2007;2:43.  Back to cited text no. 7
Reilly BJ, Leeming JM, Fraser D. Craniosynostosis in the rachitic spectrum. J Pediatr 1964;64:396-405.  Back to cited text no. 8
Vega RA, Opalak C, Harshbarger RJ, Fearon JA, Ritter AM, Collins JJ, et al. Hypophosphatemic rickets and craniosynostosis: A multicenter case series. J Neurosurg Pediatr 2016;17:694-700.  Back to cited text no. 9
Bickel H, Thursby-Pelham DC. Hyperamino-aciduria in Lignac-Fanconi disease, in galactosaemia and in an obscure syndrome. Arch Dis Child 1954;29:224-31.  Back to cited text no. 10
De Matteis MA, Staiano L, Emma F, Devuyst O. The 5-phosphatase OCRL in Lowe syndrome and dent disease 2. Nat Rev Nephrol 2017;13:455-70.  Back to cited text no. 11
Schneider JF, Boltshauser E, Neuhaus TJ, Rauscher C, Martin E. MRI and proton spectroscopy in Lowe syndrome. Neuropediatrics 2001;32:45-8.  Back to cited text no. 12
Cibis GW, Waeltermann JM, Whitcraft CT, Tripathi RC, Harris DJ. Lenticular opacities in carriers of Lowe's syndrome. Ophthalmology 1986;93:1041-5.  Back to cited text no. 13
Loi M. Lowe syndrome. Orphanet J Rare Dis 2006;1:16.  Back to cited text no. 14
Rendu J, Montjean R, Coutton C, Suri M, Chicanne G, Petiot A, et al. Functional characterization and rescue of a deep intronic mutation in OCRL gene responsible for Lowe syndrome. Hum Mutat 2017;38:152-9.  Back to cited text no. 15


  [Figure 1]

  [Table 1]


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