IGSF1 deficiency syndrome (immunoglobulin superfamily member 1) is considered the most common sex-linked cause of secondary congenital hypothyroidism and is characterized by a wide variety of other clinical and biochemical features, including hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Congenital central hypothyroidism is a rare disease (1:65,000 births); the detection of which may be delayed and missed by neonatal screening programs since most neonatal screening programs are based on TSH determination in dried blood spots only. Untreated hypothyroidism may cause abnormal liver biochemistry and non-alcoholic fatty liver disease. Our aim is to report a case of secondary hypothyroidism in an infant with an uncommon initial presentation. A 3-month-old male baby was referred to our hospital due to elevated alpha-fetoprotein levels, hypercholesterolemia, and macrosomia. Initial investigations revealed enlarged fatty liver and central hypothyroidism. Pituitary insufficiency was biochemically excluded and a pituitary MRI showed normal findings. Upon genetic analysis, a hemizygous variant NM_001170961.1:c.2422dup, p.(His808Profs*14), in IGSF1 gene was detected, establishing the diagnosis of the IGSF1 deficiency syndrome. In our patient, no other clinical findings were identified. Treatment with levothyroxine led to the remission of liver disease. Liver disease may be the initial presentation of secondary hypothyroidism in neonates and infants. Macrosomia in patients with isolated secondary central hypothyroidism is a strong indicator of IGSF1 syndrome.

Transaldolase (TALDO) deficiency (OMIM #606003) is a rare autosomal recessive multi-systemic disorder of carbohydrate metabolism. It has a vast phenotypic spectrum ranging from neonatal liver failure to slowly progressive liver cirrhosis and is characterized by intrauterine growth restriction, hepatosplenomegaly, bicytopenia, nephrolithiasis, and congenital heart disease. We report a patient with a late-onset form of TALDO deficiency characterized by hypergonadotropic hypogonadism and slightly elevated levels of alpha-fetoprotein (AFP). A novel TALDO1 mutation was detected through the application of reverse genetics with the use of clinical exome sequencing (CES). This report provides further evidence that reverse genetics is a useful approach in patients who do not manifest the hallmark features of known and recognizable syndromes. TALDO deficiency should be considered in the differential diagnosis of unexplained elevated AFP levels and hypergonadotropic hypogonadism with microlithiasis.

We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations, and to assess whether immunodeficiency and increased cancer risk are part of the DNA repair disorder caused by mutations in the PNKP gene. We evaluated nine patients with PNKP mutations. A neurological history and examination was obtained. All patients had undergone neuroimaging and genetic testing as part of the prior diagnostic process. Laboratory measurements included potential biomarkers, and, in the context of a DNA repair disorder, we performed a detailed immunologic evaluation, including B cell repertoire analysis. We identified three new mutations in the PNKP gene and confirm the phenotypic spectrum of PNKP-associated disease, ranging from microcephaly, seizures, and developmental delay to ataxia with oculomotor apraxia type 4. Irrespective of the phenotype, alpha-fetoprotein is a biochemical marker and increases with age and progression of the disease. On neuroimaging, (progressive) cerebellar atrophy was a universal feature. No clinical signs of immunodeficiency were present, and immunologic assessment was unremarkable. One patient developed cancer, but this was attributed to a concurrent von Hippel-Lindau mutation. Immunodeficiency and cancer predisposition do not appear to be part of PNKP-associated disease, contrasting many other DNA repair disorders. Furthermore, our study illustrates that the previously described syndromes microcephaly, seizures, and developmental delay, and ataxia with oculomotor apraxia type 4, represent the extremes of an overlapping spectrum of disease. Cerebellar atrophy and elevated serum alpha-fetoprotein levels are early diagnostic findings across the entire phenotypical spectrum.

Hepatocellular carcinoma (HCC) is one of the most common fatal cancer in the world and androgens are among the possible etiological factors. Congenital adrenal hyperplasia (CAH) is a group of inherited diseases caused by enzyme failure in the steroid biosynthesis of the adrenal cortex, resulting in an augmented 17-hydroxyprogesterone, androstenedione and testosterone production. While the occurrence of testicular adrenal rest tumors and adrenocortical tumors in congenital adrenal hyperplasia is well described in the literature, no data on HCC occurrence are available. A 35-years-old Italian man of Caucasian origin, affected by non-classic CAH due to partial 21-hydroxylase deficiency came to observation for revaluation of his adrenal picture. Besides common hormonal and biochemical analysis, an abdomen Magnetic Resonance Imaging was performed, resulting in an 18 mm large nodular lesion between liver segments VII and VIII. Radiological reports matched with an increased serum α-fetoprotein level. A surgical removal of the lesion was performed. After that, several recurrences of the lesion, which was consequently treated by radiofrequency ablation, occurred. Every recurrence was accompanied by an increase in testosterone and steroid hormone binding globulin serum levels. Our report suggests the need for screening of liver lesions in males affected by this syndrome.