Kenny Caffey Syndrome, Clinical and Genetic Features in Children in North Israel

The Abstract Kenny-Caffey syndrome (KCS) type 1 is a rare hereditary skeletal disorder. KCS reported almost exclusively in middle eastern populations. It is characterized by severe growth retardation-short stature, dysmorphic features, episodic hypocalcemia, hypoparathyroidism, seizures, and medullary stenosis of long bones with thickened cortices. We present here three cases with the characteristic symptoms of growth retardation, dysmorphic features, and hypoparathyroidism. After a full investigation, Kenny-Caffery Syndrome was diagnosed.


Introduction
Kenny-Caffey syndrome is a rare genetic condition causing skeletal abnormalities. The disease affects males and females in equal proportion. Inheritance may be autosomal dominant or autosomal recessive. Individuals with the condition have a shortened stature and thickened long bones. Electrolytic disturbances are prevalent, like hypocalcemia. It is a rare primary bone dysplasia syndrome characterized by cortical thickening and medullary stenosis of the long bones, growth retardation with short stature, delayed anterior fontanelle closure, facial dysmorphism micrognathia, and microphthalmia, congenital hypoparathyroidism leads to hypocalcemia. An additional manifestation is an optic atrophy, tortuous retinal vessels, dental caries, enamel defects, and, occasionally, hypoplastic nails and neonatal liver disease. [1,2] with more severe growth retardation, intellectual disability, microcephaly, and recurrent bacterial infections being observed in the latter. Kenny-Caffey syndrome type 1 (KCS 1) is a rare autosomal recessive skeletal disorder. This disease has been found almost exclusively in the Middle East. A few data available about its prevalence is in Saudi Arabia and is estimated between 1:40,000 and 1:100,000 live births [3]. In 1995 in Israel, six Bedouin families in the country were first described as having the syndrome, and they showed endocrine involvement, low stature, and secondary hypoparathyroidism; There are cases with participation of the central nervous system and the immune system and also accompanied by developmental delays.

Case 1
A two-week-old baby boy was administered to our department due to restlessness and vomiting. He was born to consanguineous parents from bedouin Origin. Patient history revealed that he was borne at term by normal vaginal delivery in a private hospital and cried immediately at birth. His birth weight was 2.5kg and length were 34.5cm. In the father's family, a number of children died at an early age due to unknown reason. On physical examination: a very small baby with facial dysmorphism. Same weight as birth weight appeared to be contaminated. Investigation to exclude sepsis was done and showed, hypocalcemia 5.2mg%, phosphorus 8.2mg%, magnesium 1.4mg%, albumin 3.5g%, the rest of the electrolytes were normal. X-ray images showed suspicion of thymus absence, considering that it is Di-George Syndrome, neck US was done and showed thymus. The baby began receiving large doses of calcium intravenous + 1 alpha vitamin 3D and magnesium sulfate.
Calcium values reached the normal levels after about 3 weeks of intra-venous treatment with 750-1000mg/kg. + 0.5 micrograms of vitamin D. The baby stabilized at calcium values between 7.5-8.5mg%. No weight gain was observed, despite proper intake of food (suction + maternity supplement). At the age of 6 months the child was readmitted and hospitalized due to cyanosis and apnea.
On his admission the infant's weight 3850g. Laboratory tests showed calcium levels 5.5g%, with phosphorus levels 9.64mg% and magnesium 1.6mg%. Complete blood count electrolytes and venous gases was normal. Intravenous calcium was applied: this time the calcium increased rapidly. follow up once a week was done in pediatric nephrology clinic. At age of 8 months, the patient's laboratory tests were normal due to daily oral calcium therapy: 2500-10,000mg/day + Vitamin 3D α1 0.5µcg/d + phosphor adsorbents. In respect of the patient's family history, Genetic consult suggested a possible hereditary disorder with autosomal recessive type of inheritance.

Case 2
A 6-month year old baby girl was administered to our hospital due to failure to thrive (FTT), she was thriving poorly in spite of her good appetite. She was the third child to consanguineous bedouin parents who had 2 children who died in childhood due to ventricular arrhythmias, due to injury to the CASQ 2 gene, and two more children passed away for an unknown reason. whereas the other siblings were normal. The baby was born after a fullterm pregnancy with no considerable maternal health issues.   Yet another similar phenotype, Kenny-Caffey syndrome type 2, is an autosomal dominant disorder due to heterozygous mutations in the FAM111A gene (family with sequence similarity 111, member A) and differs from the type 1 syndrome in its absence of mental retardation [6,7].

Differential Diagnosis of Neonatal Hypocalcaemia
Calcium is actively transferred from the mother to the fetus by a calcium pump regulated by PTHrP. The result is that in newborn calcium values are higher than in the mother, Calcium values: 10-