Patients
The study was carried out on 7 MPS IVA patients recruited in paediatric departments of different geographic areas of Tunisia (Central and Southern areas). It was approved by the Ethics Committees of the respective Tunisian hospitals, and the families gave informed consent before withdrawal of blood.
Family and history description of the 7 studied patients were summarized in table
1.
Table 1
Description of the 7 MPS IVA patientsyr: years, mo: months
Consanguinity of the parents/degree | 1st degree | 1st degree | 3rd degree | 3rd degree | 1st degree | 1st degree | 1st degree |
Age of diagnosis (yr/mo) | 3 | 8 | 3 | 5/4 | 4/5 | 7/7 | 7 |
Age of onset (yr/mo) | 18 months | 14 months | 2 | 16 months | 2/3 | 18 mo | 3 |
Sex | Male | Female | Male | Female | Female | Female | Female |
Age (yr/mo) | 15 | 13 | 9/8 | 8 | 11/7 | Died at 7yr | 14 |
Height cm (SD) | 1 m (-4.8) | 96 (-6) | 95 (-5.9) | 90 (-6.6) | 96 (-8.4) | 98 (-5) | 122 (-4) |
Weight kg (SD) | 17 (-3.2) | 14 (-3.3) | 16 (-3.1) | 15 (-2.3) | 16 (-3) | 15 (-2.3) | 26 (-2.3) |
GALNS assay (nmoles/h/mg prot) | 0.04 | 0.02 | 0.03 | Not done | 0.005 | 0.06 | 0.07 |
The patients were always consanguineous but the families completely unrelated to each other and lived far apart. All the affected children have healthy sibling(s). Patients 1 - 2 and 3 - 4 belong to the same siblings.
Patients 1
He was the second child of healthy first degree consanguineous parents originated from the South of Tunisia and no skeletal disorders had occurred in the family. The patient was delivered vaginally after an uncomplicated full-term pregnancy. He was eutrophic at birth and during the first year of life, psychomotor and mental characteristics were perfectly normal. From 18 months of age, he had progressive walking troubles with tendency to fall. At the age of 3 years, he has been operated for inguinal hernia. The surgeon revealed osseous malformations such as genu valgum, dorsal and lumbar cyphosis. At the age of 9 years, he wore an orthopedic corset without any result. Marked bone dysplasias (sternal bulge, disproportional dwarfism with short trunk and neck) with arthrochalasis associated with functional troubles and facial dysmorphism (peg shaped dentition, head rejection) led to the diagnosis of Morquio A syndrome.
Radiologic examination detected skeleton malformations on cervical rachis (flat cervical vertebra, hypoplasia of the odontoid apophysic second vertebrae), on thorax (oar-appearing ribs) and rachis. The ophtalmological examination was normal. Morquio A syndrome was based on findings of keratansulfaturia and very low level of GALNS activity in leukocytes. At the age of 15 years, the examination of the patient highlighted important osseous deformations and abdominal distension without spanchnomegalia. The neurological examination was normal. He was doing excellently in the high school, especially in maths and physics although many practical problems such as speed of writing, transportation as he still could barely walk. During the survey, we could ask for an electric handicapped adapted car to allow him to go to school easier. The patient's phenotype was classical Morquio A disease, severe form.
Patient 2
This girl of 2 years, the sibling case of patient 1 was asymptomatic when MPS IVA was confirmed by enzymatic assay with a very low GALNS activity. The vaginal delivery and the postnatal period were without any complication. Since then, the patient has developed gradually scoliosis, pectus carinatum and severe valgus deformities. She was intellectually normal but had quickly decreased motor function and barely walked from the age of 5 years, and finally could not go to school, contrary to her brother. One year later, a spastic paraplegia occurred. Cervical MRI showed a cervical spine compression. After performing surgery stabilizing the upper cervical spine, she had partially recovered.
Patient 3
Patient 3 appeared perfectly normal at birth after vaginal delivery. His father was married with his cousin's daughter. At the age of 3 years, the patient had a waddling gate with a tendency to fall, that required medical studies at paediatric unit of Kairouan hospital (central Tunisia). Marked growth retardation, facial dysmorphism with a particular protrusion, bone dysplasias, short trunk and neck, sternal bulge, disproportional dwarfism led to the clinical diagnosis of Morquio syndrome. Keratane sulfaturia was detected and enzyme assay revealed MPS IVA. At the age of 8 years, further skeletal X-rays investigation typically showed marked flattening of the vertebra, oar-appearing ribs, cyphosis with generalized platyspondylia. Cardiac examination detected and left ventricular hypertrophy.
Neurological investigation was normal in spite a relative retardation in school performances which may be explained by hearing impairment.
Patient 4
she had no symptom except slight thoracic deformation when she was studied at 16 months because of the disease in her brother, patient 3. Biochemical investigations detected keratosulfaturia and a very low level of GALNS activity, leading to Morquio A syndrome. She was treated surgically for tibia osteotomy because of an intense genu valgum which avoided her to walk. Then, the clinical course was similar to her brother's. Gradually, facial dysmorphim and disproportional dwarfism developed. At the age of 5 years, radiographs detected truncal dysmorphim and dorsal-lumbar cyphosis with generalized platyspondylia. Intellectually, the patient was normal and doing well at school.
Patient 5
This little girl whose parents were first cousin was the first child, after a normal vaginal delivery. At the age of 4 years, she was referred to paediatric Unit of Kairouan Hospital (Central Tunisia) for medical investigation of severe dysmorphic syndrome.
Retrospectively, the onset of the disease could be ascertained to 2 years of age with abnormal prominence of the breastbone. Gradually, valgus deformities of the knees, funnel like chest with carinate pectus developed associated with characteristic facial appearance (broad mouth, small nose) and abnormal flexibility of joints. The Morquio A diagnosis was confirmed by keratansulfaturia and deficient activity of GALNS in leukocytes. By the age of 8 years, compensatory upper thoracal lower thoraco-lumbar scoliosis and cervicothoracal cyphosis developed. They resulted in progressive shortening of the walking distance and fatigue. Skeletal radiographs showed severe dysostosis, generalized platyspondylia, and important anterior hypoplasia of L1. Cervical MRI indicated compression of the medulla.
Aspastic paraplegia occurred by the age of 10 years and the surgeons refused to perform any operation. Now, hepatomegaly, mitral insufficiency and cornal clouding have developed. Her severe handicap avoided her to go to school, although her intelligence was preserved. In addition, very low socio economical conditions result in extremely bad conditions of life for the child and the whole family.
Patient 6
She was the third child born to consanguineous family, after a normal vaginal delivery. By the age of 18 months, this child was evaluated for growth failure, feel walking problems and intensive genu valgum at paediatric department of Sidi Bouzid Hospital in central Tunisia. Associated with facial dysmorphism (protrusion of lower facial maxillary) but normal dentition, the trunk was short and pectus carinatum was observed. She was diagnosed as MPS IVA on the basis of clinical analysis and the diagnosis was demonstrated by biochemical analysis (keratansulfaturia and no detectable activity of GALNS in leukocytes).
At the age of 7 years, skeletal X-rays and cervical magnetic resonance imaging (MRI) typically showed acute osseous deformation with dorsal and lumbar cyphosis. The vertebra was markly flattening and the connection between first and second vertebra in the neck was extremely poorly developed with a compression of the bulbospinal region. Her intelligence was normal and she was studying well at the first year of school. The overall physical handicap was severe and she eventually died few days after spinal deformity surgical treatment, during the molecular study.
Patient 7
She was the third child born to consanguineous family and she had 2 MPS IVA unaffected brothers. By the age of 3 years, this girl was referred to paediatric unit of Tunis (north of Tunisia). She was evaluated for facial dysmorphism, protrusion, bone dysplasias, short trunk and neck, sternal bulge and disproportional dwarfism. At the age of 7 years, skeletal X-rays and cervical magnetic resonance imaging (MRI) typically showed acute osseous deformation with dorsal and lumbar cyphosis. By the age of 11 years, radiologic examination detected skeleton malformations on cervical rachis (flat cervical vertebra, hypoplasia of the odontoid apophysic second vertebrae), on thorax (oar-appearing ribs) and rachis. Cardiac examination was normal. Her intelligence was normal and she was studying well at school.