Hyperphosphatasia with Impaired Intellectual Development Syndrome (HPMRS), first described by Mabry et al. [1], represents a group of rare inherited disorders caused by defects in GPI-anchor biosynthesis [1]. Mutations in PIGV, PIGO, PGAP2, PGAP3, PIGW, PIGY, and PIGL disrupt the attachment of ALP and other GPI-anchored proteins to the cell surface, leading to persistent hyperphosphatasemia [2-4].

Clinically, HPMRS is characterized by moderate-to-severe intellectual disability, seizures, hypotonia, distinctive facial features, brachytelephalangy, feeding difficulties, and sometimes congenital heart or gastrointestinal anomalies [5-7]. The severity varies according to the affected gene. We report the first genetically confirmed case of HPMRS from Iraq, emphasizing its clinical, biochemical, and genetic findings to raise awareness of this underrecognized condition.

Case Presentation

Patient Information

• Name: Lababa Hassan Ali

• Age: 18 months

• Address: Taza, Kirkuk, Iraq

• Date of Admission: 29 July 2025

• Date of History and Examination: 31 July 2025

Chief Complaint

Recurrent abnormal body movements manifested as generalized tonic–clonic seizures associated with eye rolling, frothy secretions, and loss of consciousness lasting approximately four minutes, occurring three times daily.

History of Present Illness

The  patient  was  a  preterm  infant diagnosed with genetically  confirmed  HPMRS-1 (PIGV mutation) at 12     

months. She had been on regular neurological follow-up and received valproate, brivaracetam, lacosamide, and pyridoxine, yet seizures persisted. Two weeks before admission, she was hospitalized for chest infection and seizure exacerbation; vitamin B6 was added, but seizure frequency increased without fever, vomiting, or trauma.

Past Medical History

• Feeding difficulties and irritability since birth.

• At 4 months: absent eye contact; MRI showed cerebral atrophy; ophthalmology confirmed cortical blindness.

• At 5 months: recurrent infantile spasms evolving into generalized seizures.

• At 1 year: Whole-exome sequencing confirmed PIGV mutation.

   

Figure 1: Facial features of the patient with HPMRS (Mabry syndrome) Frontal view showing characteristic craniofacial dysmorphism including a broad forehead, thick eyebrows, long eyelashes, and a flat nasal bridge

Figure 2: Hands and feet deformities

Short, broad hands and feet with clenched fingers and bilateral clubfoot, consistent with skeletal anomalies described in HPMR

• Multiple hospitalizations for seizure control.

• Congenital heart disease (ASD) repaired surgically at 1 year.

Developmental History

Severe global developmental delay: bedridden, unable to sit, crawl, or stand; no purposeful grasp, speech, or social interaction.

Family History

• First child of non-consanguineous, healthy parents.

• No family history of epilepsy or genetic disorders.

• Anthropometry: Weight 10 kg (25th centile), length 77 cm (10th), OFC 47 cm (75th).

• Other systemic examinations were unremarkable.

Figure 3: Brain MRI of the patient

Axial T2-weighted MRI demonstrating diffuse cerebral atrophy with widened sulci and ventricular dilatation

Figure 4: Pedigree and genetic analysis

Family pedigree and Sanger sequencing confirming the pathogenic homozygous PIGV mutation in the proband; both parents are heterozygous carriers

Figure 5: Comprehensive management plan

Summary of the multidisciplinary management including antiepileptic regimen (valproate, brivaracetam, lacosamide, pyridoxine), physiotherapy, nutritional support, and genetic counseling

Figure 6: Genetic testing report – Farabi Medical Laboratory Page displaying methodology and limitations of the supplemental gene sequencing confirming GPI-anchor pathway mutation analysis performed in Erbil, Iraq

Examination Findings

• General: Unresponsive, afebrile; no pallor or cyanosis.

• Craniofacial: Broad forehead, thick eyebrows, long eyelashes, flat nasal bridge.

• Skeletal: Short broad hands/feet, clenched fists, bilateral clubfoot.

• Neurological: Cortical blindness, generalized hypotonia, muscle power 3/6, decreased reflexes.

• Anthropometry: Weight 10 kg (25th centile), length 77 cm (10th), OFC 47 cm (75th).

• Other systemic examinations were unremarkable.

Figure 7: Whole-Exome Sequencing (WES) result – Genox Genetic Diagnostic Center Genetic report confirming a homozygous missense variant c.1231C>T (p.Pro411Ser) in  the  PIGV  gene, consistent with the diagnosis of HPMRS-1

Figure 8: Carrier testing report of the patient’s father – Farabi Medical Laboratory Variant confirmation study showing heterozygous carrier status for the PIGV c.1231C>T (p.Pro411Ser) variant, supporting an autosomal recessive inheritance pattern

Investigations

• Serum ALP: Persistently elevated (2–20× upper limit).

• Brain MRI: Cerebral atrophy.

• Genetic Testing: Pathogenic PIGV mutation, confirming HPMRS-1.

Figure 10: Facial features of the patient with HPMRS (Mabry syndrome) Frontal photograph showing coarse facial appearance with a broad forehead, thick eyebrows, long eyelashes, full cheeks, and a flat nasal bridge, typical of PIGV-related HPMRS.

This case expands the global literature on HPMRS, representing the first genetically confirmed Iraqi patient. The triad of refractory epilepsy, severe developmental delay, and persistent hyperphosphatasemia strongly suggested a GPI-anchor defect [3]. Early genetic confirmation ensures accurate diagnosis, family counseling, and avoidance of unnecessary procedures [8]. Pathophysiology: The elevated ALP is due to defective membrane anchoring of GPI-linked proteins, especially ALP, causing increased enzyme shedding into circulation [9]. PIGV, the gene mutated in HPMRS-1, encodes mannosyltransferase catalyzing the fifth step of GPI-anchor synthesis [4,9]. Similar biochemical mechanisms are shared by PIGO and PGAP2/3 mutations [5,6].

Clinical Correlation

Our patient’s manifestations—severe hypotonia, seizures, craniofacial dysmorphism, cortical blindness, and skeletal deformities—are consistent with previously reported PIGV-related cases [4,6,10]. Congenital heart disease (ASD) has occasionally been described in this subtype [7,11].

Differential Diagnosis

• CHIME syndrome (OMIM 280000), caused by PIGL mutations, shares intellectual disability, seizures, and facial anomalies but includes coloboma, ichthyosis, and ear malformations, which were absent in our case [12,13].

• Benign transient hyperphosphatasemia shows isolated ALP elevation without neurological involvement [14].

Figure 11: Skeletal deformities of the upper and lower limbs

Photographs showing short, broad hands with clenched fingers (upper image) and bilateral clubfoot deformities (lower image), consistent with skeletal abnormalities described in HPMRS.

• Juvenile Paget disease presents with bone deformities and hearing loss but normal intellect [15].

Therapeutic considerations: While no curative treatment exists, supportive measures such as physiotherapy, nutritional management, and seizure optimization remain essential [8,10]. Some patients benefit from pyridoxine supplementation, reflecting ALP’s role in vitamin B6 metabolism [16]. Our patient, however, showed limited response.

Epidemiologic Significance: 

HPMRS accounts for less than 0.5% of developmental disorders [3], yet early recognition using elevated ALP as a screening clue followed by exome sequencing can establish diagnosis, especially in low-resource settings [17]. Reporting such cases enriches global understanding of genotype-phenotype correlations and may promote earlier detection across the Middle East.

This is the first genetically confirmed case of HPMRS (PIGV mutation) from Iraq. Persistent hyperphosphatasemia with developmental delay and seizures should prompt consideration of GPI-anchor biosynthesis defects. Early diagnosis is vital for genetic counseling and appropriate multidisciplinary care.

1. Mabry, C.C., et al. “Familial Hyperphosphatasia with Mental Retardation, Seizures, and Neurologic Deficit.” Journal of Pediatrics, vol. 77, no. 1, 1970, pp. 74–85.

2. Krawitz, P.M., et al. “PIGV Mutations Cause Hyperphosphatasia with Mental Retardation Syndrome Type 1 (HPMRS1).” Nature Genetics, vol. 42, no. 7, 2010, pp. 555–559.

3. Knaus, A., et al. “Characterization of Glycosylphosphatidylinositol Anchor Biosynthesis Defects.” Journal of Inherited Metabolic Disease, vol. 41, no. 3, 2018, pp. 495–505.

4. Nguyen, T.T.M., et al. “PIGV Gene Mutations and Clinical Spectrum of HPMRS.” Clinical Genetics, vol. 95, no. 6, 2019, pp. 716–725.

5. Fujita, M., et al. “PIGO Mutations in Hyperphosphatasia with Mental Retardation Syndrome Type 2.” American Journal of Human Genetics, vol. 91, no. 1, 2012, pp. 146–151.

6. Hansen, L., et al. “PGAP2 and PGAP3 Mutations in GPI-Anchor Deficiencies.” Human Mutation, vol. 34, no. 1, 2013, pp. 146–152.

7. Martin, H.C., et al. “Clinical Spectrum and Genetics of Congenital GPI-Anchor Deficiencies.” Genetics in Medicine, vol. 19, no. 9, 2017, pp. 986–994.

8. Brady, P.D., et al. “Diagnostic Utility of Whole-Exome Sequencing in Neurodevelopmental Disorders.” Clinical Genetics, vol. 99, no. 1, 2021, pp. 90–100.

9. Hong, Y., et al. “Biosynthesis of GPI Anchors and Their Defects.” FEBS Letters, vol. 594, no. 1, 2020, pp. 3–22.

10. Ranza, E., et al. “PIGV-Related Mabry Syndrome: Expanded Phenotype and Management.” European Journal of Medical Genetics, vol. 64, no. 9, 2021, article 104297.

11. Ng, B.G., and H.H. Freeze. “Perspectives on Congenital Disorders of Glycosylation and GPI-Anchor Biosynthesis.” Glycobiology, vol. 28, no. 9, 2018, pp. 623–640.

12. Ng, B.G., et al. “Mutations in PIGL Cause CHIME Syndrome.” American Journal of Human Genetics, vol. 90, no. 4, 2012, pp. 685–688.

13. Wang, H., et al. “Phenotypic Overlap between CHIME and HPMRS Syndromes Due to PIGL Variants.” Molecular Genetics and Metabolism Reports, vol. 32, 2022, article 100923.

14. Kraut, J.R., et al. “Benign Transient Hyperphosphatasemia of Infancy and Early Childhood.” Journal of Pediatrics, vol. 106, no. 5, 1985, pp. 718–722.

15. Whyte, M.P., et al. “Juvenile Paget’s Disease: Molecular and Clinical Findings.” Bone, vol. 59, 2014, pp. 143–153.

16. Murakami, Y., et al. “Pyridoxine-Responsive Seizures and GPI Anchor Defects.” Brain and Development, vol. 40, no. 3, 2018, pp. 226–233.

17. Richards, S., et al. “Standards and Guidelines for the Interpretation of Sequence Variants.” Genetics in Medicine, vol. 17, no. 5, 2015, pp. 405–424.