**3.1 Hydrops-ectopic calcification-moth-eaten skeletal dysplasia**

Most proximal in the post-squalene pathway is hydrops-ectopic calcification-motheaten (HEM) skeletal dysplasia, or Greenberg dysplasia. This very rare and severe autosomal recessive disorder was first described in 1988 [40] with only 11 examples identified in the literature to date. All but one of these have been lethal *in utero*, with the remaining case dying at 2 days of age [41]. HEM skeletal dysplasia is characterised by significant non-immune hydrops fetalis, erroneous chondro-osseous calcification of vertebrae, ribs, pelvis, larynx and trachea as well as a diagnostic mottled 'moth-eaten' appearance of long bones on radiography [42–44]. Further skeletal abnormalities can include rhizomelic and mesomelic shortening of the limbs, platyspondyly, decreased skull ossification and distal dysmorphisms such as absent phalanges or postaxial polydactyly [42–45]. Non-skeletal congenital malformations include pulmonary hypoplasia, intestinal malrotation, cystic hygroma and excessive extramedullary haematopoiesis [45, 46]. Histology shows significant bone and cartilage disorganisation [43, 45].

HEM skeletal dysplasia was first suggested as an inborn error of cholesterol biosynthesis by Kelley et al. [47] with identification of increased levels of 4,4-dimethylcholesta-8 [9],14-dien-3β-ol and 4,4-dimethylcholesta-8(9),14,24 trien-3β-ol in cultured fibroblasts, indicating a deficiency of sterol ∆14-reductase. This enzyme converts these sterols to 4,4-dimethylcholesta-8(9)-en-3β-ol and 4,4-dimethylcholesta-8(9),24-dien-3β-ol, respectively. This point on the cholesterol biosynthesis pathway is unique with sterol ∆14-reductase activity by both the lamin B receptor (LBR) and a second enzyme DHCR14 (TM7FS2), although functional redundancy is disputed [48, 49]. It was originally thought that the more prominent role in sterol biosynthesis was that of DHCR14 compared to the lamin B receptor. However, it has more recently been demonstrated that it is a deficiency in the lamin B receptor due to mutations in *LBR* at 1q42.12 that is causative for HEM skeletal dysplasia [50, 51] and that it is the LBR, not DHCR14, that is required for cholesterol biosynthesis [48, 52].

The involvement of *LBR* has raised contention as to whether HEM skeletal dysplasia should be classified as a laminopathy rather than as an error of cholesterol synthesis [49]; however, it is appropriate to recognise that mutations in *LBR* can cause different disorders in different contexts. The type of mutation (missense, nonsense or splice-site), the functional location of each mutation in the *LBR* gene and the residual protein activity affect the clinical outcome of this disorder [53, 54]. The LBR protein has both a nuclear domain involved in anchoring chromatin to the nuclear membrane, and a transmembrane domain with sterol ∆14-reductase activity critical for cholesterol synthesis [48], the latter primarily where mutations causing HEM dysplasia are located [50]. Some mutations found in *LBR* in HEM dysplasia patients have been identified in the heterozygous state in the relatively benign autosomal dominant condition of Pelger-Huët anomaly in which granulocytes have bilobed nuclei but patients are otherwise clinically normal. These two conditions may represent different allele patterns of the same disorder for some mutations [53, 55]. The less common homozygous Pelger-Huët is clinically more severe with round or ovoid granulocyte nuclei and some cases with mild skeletal abnormalities [56, 57]. This highlights the role of the lamin B receptor sterol reductase function as essential in prenatal development but also the phenotypic continuum that can occur for various allele combinations of the *LBR* gene.

Species variation with respect to the role of the LBR can make mouse model outcomes difficult to elucidate. Studies of mutations in both *LBR* and *DHCR14/ TM7FS2* have been investigated in ichthyosis (*ic*) mice with contrasting conclusions, including those highlighted above and as reviewed by Herman and Kratz [58].
